Sulfonyl-substituted bicyclic compounds as modulators of PPAR

ABSTRACT

Compounds as modulators of peroxisome proliferator activated receptors, pharmaceutical compositions comprising the same, and methods of treating disease using the same are disclosed.

This application is a divisional of U.S. application Ser. No.11/258,463, filed Oct. 25, 2005, which claims priority to U.S.Provisional Applications No. 60/623,252, filed Oct. 29, 2004, and No.60/079,813, filed May 11, 2005; all of which are hereby incorporated byreference as if written herein in their entireties.

FIELD OF THE INVENTION

The present invention relates to novel sulfonyl-substituted bicyclicaryl derivatives and methods for treating various diseases by modulationof nuclear receptor mediated processes using these compounds, and inparticular processes mediated by peroxisome proliferator activatedreceptors (PPARs).

BACKGROUND OF THE INVENTION

Peroxisome proliferators are a structurally diverse group of compoundswhich, when administered to mammals, elicit dramatic increases in thesize and number of hepatic and renal peroxisomes, as well as concomitantincreases in the capacity of peroxisomes to metabolize fatty acids viaincreased expression of the enzymes required for the β-oxidation cycle(Lazarow and Fujiki, Ann. Rev. Cell Biol. 1:489-530 (1985); Vamecq andDraye, Essays Biochem. 24:1115-225 (1989); and Nelali et al., CancerRes. 48:5316-5324 (1988)). Compounds that activate or otherwise interactwith one or more of the PPARs have been implicated in the regulation oftriglyceride and cholesterol levels in animal models. Compounds includedin this group are the fibrate class of hypolipidemic drugs, herbicides,and phthalate plasticizers (Reddy and Lalwani, Crit. Rev. Toxicol.12:1-58 (1983)). Peroxisome proliferation can also be elicited bydietary or physiological factors such as a high-fat diet and coldacclimatization.

Biological processes modulated by PPAR are those modulated by receptors,or receptor combinations, which are responsive to the PPAR receptorligands. These processes include, for example, plasma lipid transportand fatty acid catabolism, regulation of insulin sensitivity and bloodglucose levels, which are involved in hypoglycemia/hyperinsulinemia(resulting from, for example, abnormal pancreatic beta cell function,insulin secreting tumors and/or autoimmune hypoglycemia due toautoantibodies to insulin, the insulin receptor, or autoantibodies thatare stimulatory to pancreatic beta cells), macrophage differentiationwhich lead to the formation of atherosclerotic plaques, inflammatoryresponse, carcinogenesis, hyperplasia, and adipocyte differentiation.

Subtypes of PPAR include PPAR-alpha, PPAR-delta (also known as NUC1,PPAR-beta and FAAR) and two isoforms of PPAR-gamma. These PPARs canregulate expression of target genes by binding to DNA sequence elements,termed PPAR response elements (PPRE). To date, PPRE's have beenidentified in the enhancers of a number of genes encoding proteins thatregulate lipid metabolism suggesting that PPARs play a pivotal role inthe adipogenic signaling cascade and lipid homeostasis (H. Keller and W.Wahli, Trends Endoodn. Met. 291-296, 4 (1993)).

Insight into the mechanism whereby peroxisome proliferators exert theirpleiotropic effects was provided by the identification of a member ofthe nuclear hormone receptor superfamily activated by these chemicals(Isseman and Green, Nature 347-645-650 (1990)). The receptor, termedPPAR-alpha (or alternatively, PPARα), was subsequently shown to beactivated by a variety of medium and long-chain fatty acids and tostimulate expression of the genes encoding rat acyl-CoA oxidase andhydratase-dehydrogenase (enzymes required for peroxisomal β-oxidation),as well as rabbit cytochrome P450 4A6, a fatty acid ω-hydroxylase(Gottlicher et al., Proc. Natl. Acad. Sci. USA 89:4653-4657 (1992);Tugwood et al., EMBO J 11:433-439 (1992); Bardot et al., Biochem.Biophys. Res. Comm. 192:37-45 (1993); Muerhoff et al., J. Biol. Chem.267:19051-19053 (1992); and Marcus et al., Proc. Natl. Acad. Sci. USA90(12):5723-5727 (1993).

Activators of the nuclear receptor PPAR-gamma (or alternatively, PPARγ),for example troglitazone, have been clinically shown to enhanceinsulin-action, to reduce serum glucose and to have small butsignificant effects on reducing serum triglyceride levels in patientswith Type 2 diabetes. See, for example, D. E. Kelly et al., Curr. Opin.Endocrinol. Diabetes, 90-96, 5 (2), (1998); M. D. Johnson et al., Ann.Pharmacother., 337-348, 32 (3), (1997); and M. Leutenegger et al., Curr.Ther. Res., 403-416, 58 (7), (1997).

The third subtype of PPAR, PPAR-delta (or alternatively, PPARδ, PPARβ,or NUC1) initially received much less attention than the other PPARsbecause of its ubiquitous expression and the unavailability of selectiveligands. However, genetic studies and recently developed syntheticPPAR-δ agonists have helped reveal its role as a powerful regulator offatty acid catabolism and energy homeostasis. Studies in adipose tissueand muscle have begun to uncover the metabolic functions of PPAR-δ.Transgenic expression of an activated form of PPAR-δ in adipose tissueproduces lean mice that are resistant to obesity, hyperlipidemia andtissue steatosis induced genetically or by a high-fat diet. Theactivated receptor induces genes required for fatty acid catabolism andadaptive thermogenesis. Interestingly, the transcription of PPAR-γtarget genes for lipid storage and lipogenesis remain unchanged. Inparallel, PPAR-δ-deficient mice challenged with a high-fat diet showreduced energy uncoupling and are prone to obesity. Together, these dataidentify PPAR-δ as a key regulator of fat-burning, a role that opposesthe fat-storing function of PPAR-γ. Thus, despite their closeevolutionary and structural kinship, PPAR-y and PPAR-δ regulate distinctgenetic networks. In skeletal muscle, PPAR-δ likewise upregulates fattyacid oxidation and energy expenditure, to a far greater extent than doesthe lesser-expressed PPAR-α. (Evans R M et al 2004 Nature Med 1-7, 10(4), 2004)

PPARδ is broadly expressed in the body and has been shown to be avaluable molecular target for treatment of dyslipidemia and otherdiseases. For example, in a recent study in insulin-resistant obeserhesus monkeys, a potent and selective PPARδ compound was shown todecrease VLDL and increase HDL in a dose response manner (Oliver et al.,Proc. Natl. Acad. Sci. U.S.A. 98: 5305, 2001). Also, in a recent studyin wild-type and HDL-lacking, ABCA1^(−/−) mice, a different potent andselective PPARδ compound was shown to reduce fractional cholesterolabsorption in the intestine, and coincidentally reduce expression of thecholesterol-absorption protein NPC1L1 (van der Veen et al., J. LipidRes. 2005 46: 526-534).

Because there are three isoforms of PPAR and all of them have been shownto play important roles in energy homeostasis and other importantbiological processes in human body and have been shown to be importantmolecular targets for treatment of metabolic and other diseases (seeWilson, et al. J. Med. Chem. 43: 527-550 (2000)), it is desired in theart to identify compounds which are capable of interacting with multiplePPAR isoforms or compounds which are capable of selectively interactingwith only one of the PPAR isoforms. Such compounds would find a widevariety of uses, such as, for example, in the treatment or prevention ofobesity, for the treatment or prevention of diabetes, dyslipidemia,metabolic syndrome X and other uses.

Several PPAR-modulating drugs have been approved for use in humans.Fenofibrate and gemfibrozil are PPARα modulators; pioglitazone (Actos,Takeda Pharmaceuticals and Eli Lilly) and rosiglitazone (Avandia,GlaxoSmithKline) are PPARγ modulators. All of these compounds haveliabilities as potential carcinogens, however, having been demonstratedto have proliferative effects leading to cancers of various types(colon; bladder with PPARα modulators and liver with PPARγ modulators)in rodent studies. Therefore, a need exists to identify modulators ofPPARs that lack these liabilities.

Additionally, recent evidence points to a role for PPAR-δ in thedevelopment of cancers, including colon, skin, and lung cancers.Modulators of PPAR could therefore find use in the treatment of cancersof various types.

SUMMARY OF THE INVENTION

The present invention relates to sulfonyl-substituted bicycliccompounds, useful as modulators of PPAR and methods of treatingmetabolic disorders. One embodiment of the invention are compoundshaving structural Formula (I)

Or a salt, ester, or prodrug thereof, wherein;

A is a saturated or unsaturated hydrocarbon chain or aheteroatom-comprising hydrocarbon chain having from 3 to 5 atoms,forming a five- to seven-membered ring;

T is selected from the group consisting of —C(O)OH, —C(O)NH₂, andtetrazole;

G₁ is selected from the group consisting of —(CR¹R²)_(n)—,—Z(CR¹R²)_(n)—, —(CR¹R²)_(n)Z—, —(CR¹R²)_(r)Z(CR¹R²)_(s)—;

Z is O, S or NR;

n is 0, 1, or 2;

r and s are independently 0 or 1;

R¹ and R² are independently selected from the group consisting ofhydrogen, halo, optionally substituted lower alkyl, optionallysubstituted lower heteroalkyl, optionally substituted lower alkoxy, andlower perhaloalkyl or together may form an optionally substitutedcycloalkyl;

X₁, X₂, and X₃ are independently selected from the group consisting ofhydrogen, optionally substituted lower alkyl, optionally substitutedcycloalkyl, halogen, perhaloalkyl, hydroxy, optionally substituted loweralkoxy, nitro, cyano, and NH₂;

G₂ is selected from the group consisting of a saturated or unsaturatedcycloalkyl or heterocycloalkyl linker, optionally substituted with X₄and X₅;

X₄ and X₅ are independently selected from the group consisting ofhydrogen, optionally substituted lower alkyl, halogen, lowerperhaloalkyl, hydroxy, optionally substituted lower alkoxy, nitro,cyano, NH₂, and CO₂R;

R is selected from the group consisting of optionally substituted loweralkyl and hydrogen;

G₃ is selected from the group consisting of a bond, a double bond, —(CR³R⁴)_(m)—, carbonyl, and —(C R³R⁴)_(m)CR³═CR⁴—;

m is 0, 1, or 2;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, optionally substituted lower alkyl, optionally substitutedlower alkoxy, optionally substituted aryl, lower perhaloalkyl, cyano,and nitro;

G₄ is selected from the group consisting of hydrogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, optionally substituted cycloheteroalkyl,optionally substituted cycloheteroaryl, optionally substitutedcycloalkenyl, and —N═(CR⁵R⁶); and

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedcycloalkenyl, and optionally substituted cycloheteroalkyl.

The present invention also provides for pharmaceutical compositionscomprising the compounds of the invention together with apharmaceutically acceptable diluent or carrier.

The present invention also discloses that bicyclic moieties substitutedwith an acid or ester moiety and a sulfonyl moiety can modulate at leastone peroxisome proliferator-activated receptor (PPAR) function.Compounds described herein may be modulating both PPAR-delta andPPAR-gamma or PPAR-alpha and PPAR-delta, or all three PPAR subtypes, orselectively modulating predominantly PPAR-gamma, PPAR-alpha orPPAR-delta. Thus, the present invention provides for a method ofmodulating PPAR comprising contacting said PPAR with a compound of theinvention. In certain preferred embodiments, said modulation isselective for PPARδ over PPARα and PPARγ. In certain more preferredembodiments, said modulation of PPARδ is 100-fold selective or greaterover said other isoforms. Most preferably, said modulation is 200- to500-fold selective over said other isoforms.

The present invention also relates to a method of modulating at leastone peroxisome proliferator-activated receptor (PPAR) functioncomprising the step of contacting the PPAR with a compound of Formula I,as described herein. The change in cell phenotype, cell proliferation,activity of the PPAR, expression of the PPAR or binding of the PPAR witha natural binding partner may be monitored. Such methods may be modes oftreatment of disease, biological assays, cellular assays, biochemicalassays, or the like.

The present invention also describes methods of treating a diseasecomprising identifying a patient in need thereof, and administering atherapeutically effective amount of a compound of Formula I, asdescribed herein, to the patient. Thus, in certain embodiments, thedisease to be treated by the methods of the present invention isselected from the group consisting of obesity, diabetes,hyperinsulinemia, metabolic syndrome X, polycystic ovary syndrome,climacteric, disorders associated with oxidative stress, inflammatoryresponse to tissue injury, pathogenesis of emphysema,ischemia-associated organ injury, doxorubicin-induced cardiac injury,drug-induced hepatotoxicity, atherosclerosis, and hypertoxic lunginjury. In another aspect, the present invention relates to a method ofmodulating at least one peroxisome proliferator-activated receptor(PPAR) function comprising the step of contacting the PPAR with acompound of Formula I, as described herein. The change in cellphenotype, cell proliferation, activity of the PPAR, or binding of thePPAR with a natural binding partner may be monitored. Such methods maybe modes of treatment of disease, biological assays, cellular assays,biochemical assays, or the like. In certain embodiments, the PPAR may beselected from the group consisting of PPARα, PPARδ, and PPARγ.

DETAILED DESCRIPTION OF THE INVENTION

In certain embodiments, the invention provides compounds of Formula Iwherein T is —C(O)OH.

In other embodiments, the invention provides compounds of Formula Iwherein A has three atoms and forms a five-membered ring.

In related embodiments, at least one of said three atoms of A is aheteroatom selected from the group consisting of N, O, and S.

In other embodiments, the invention provides compounds of Formula Ihaving structural formulae selected from the group consisting of:

In other embodiments, the invention provides compounds of Formula Ihaving structural formula (III) selected from the group consisting of:

In other embodiments, the invention provides compounds of Formula Ihaving structural formula (IV) selected from the group consisting of:

In other embodiments, the invention provides compounds of Formula Ihaving structural formula selected from the group consisting of:

In other embodiments, the invention provides compounds of Formula Ihaving structural formula selected from the group consisting of:

In certain embodiments, the invention provides compounds Formula Iwherein:

G₁ is —(CR¹R²)_(n)—;

With the proviso that if A is a 5 carbon chain, n is 0 or 1;

G₂ has the structure:

Y₁ and Y₂ are independently selected from the group consisting of N andC—X₆;

X₄ and X₅ are independently selected from the group consisting ofhydrogen, optionally substituted lower alkyl, halogen, lowerperhaloalkyl, hydroxy, optionally substituted lower alkoxy, nitro,cyano, NH₂, and CO₂R, or X₄ and X₅ together may form a carbocycle;

R is selected from the group consisting of lower alkyl and hydrogen;

p is 1, 2 or 3;

W is selected from the group consisting of —CX₄X₅- and N—X₇;

X₄ and X₅ are independently selected from the group consisting ofhydrogen, optionally substituted lower alkyl, halogen, lowerperhaloalkyl, hydroxy, optionally substituted lower alkoxy, nitro,cyano, NH₂, and CO₂R;

X₆ is selected from the group consisting of hydrogen, alkyl, hydroxy,alkoxy, cyano, halogen, lower perhaloalkyl and NH₂ or null when forminga double bond with an adjacent ring atom; and

X₇ is selected from the group consisting of hydrogen, alkyl, hydroxy,and lower perhaloalkyl, or null when forming a double bond with Y₂.

In certain preferred embodiments, the invention provides compoundsFormula I wherein p is 2, W is —CX₄X₅—, and Y₁ is N. In other preferredembodiments, p is 2, W is —CX₄X₅—, and Y₁ and Y₂ are N.

In certain embodiments, the invention provides compounds of Formula Iwherein G₁ is —(CR¹R²)_(n)—. In certain preferred embodiments, n is 0or 1. In other preferred embodiments, R¹ and R² may be independentlyselected from the group consisting of hydrogen, methyl, ethyl, andpropyl, or together may form a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. In even more preferred embodiments, R¹ and R² are hydrogen.

In certain embodiments, the invention provides compounds of Formula Iwherein G₃ is a bond.

In certain embodiments, the invention provides compounds of Formula Iwherein G₄ is selected from the group consisting of optionallysubstituted aryl and optionally substituted heteroaryl. In certainpreferred embodiments, G₄ may be optionally substituted phenyl oroptionally substituted pyridinyl. In even more preferred embodiments, G₄may be singly or doubly substituted with halogen, lower alkyl, lowerperhaloalkyl, lower haloalkoxy, or lower perhaloalkoxy. In relatedembodiments, G₄ may have a structural formula selected from the groupconsisting of:

wherein:

q is 1 to 3;

X₈ and X₉ are independently selected from the group consisting ofhydrogen, alkyl, halogen, lower perhaloalkyl, lower perhaloalkoxy ormono- or di-haloalkoxy, hydroxy, alkoxy, nitro, cyano, NH₂, and CO₂R;and

R is selected from the group consisting of lower alkyl and hydrogen.

In certain preferred embodiments, the invention provides compounds ofFormula I having structural formulae selected from the group consistingof:

wherein G₁ is selected from the group consisting of —(CR¹R²)_(n)— and—(CR¹R²)_(n)O—, and other groups are as previously defined.

In certain preferred embodiments, the invention provides compounds ofFormula I wherein X₁, X₂, and X₃ are independently selected from thegroup consisting of hydrogen, halogen, lower alkyl, and lower alkoxy. Incertain preferred embodiments, X₁, X₂, and X₃ are independently selectedfrom the group consisting of hydrogen, methyl, ethyl, propyl, andhalogen. In other preferred embodiments, X₁, X₂, and X₃ may beindependently selected from the group consisting of hydrogen and methyl.

Another aspect of the invention are pharmaceutical compositionscomprising compounds of Formula I together with pharmaceuticallyacceptable diluents or carriers.

The present invention discloses that novel compounds of Formula I,disclosed herein, can modulate at least one peroxisomeproliferator-activated receptor (PPAR) function. Compounds describedherein may be activating both PPARδ and PPARγ or PPARα and PPARδ, or allthree PPAR subtypes, or selectively activating predominantly PPARγ,PPARα or PPARδ.

Thus, in one aspect, the present invention discloses a method ofmodulating at least one peroxisome proliferator-activated receptor(PPAR) function comprising the step of contacting the PPAR with acompound of Formula I, as described herein. The change in cellphenotype, cell proliferation, activity of the PPAR, expression of thePPAR or binding of the PPAR with a natural binding partner may bemonitored. Such methods may be modes of treatment of disease, biologicalassays, cellular assays, biochemical assays, or the like.

In another aspect, the present invention discloses methods of treatmentof a PPAR-delta mediated disease or condition comprising identifying apatient in need, administering a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt, ester,amide, or prodrug thereof. In certain embodiments of this aspect, thepresent invention discloses methods: for raising HDL, lowering LDLc,shifting LDL particle size from small dense to normal LDL, or inhibitingcholesterol absorption in a subject; for decreasing insulin resistanceor lowering blood pressure in a subject; for treating obesity, diabetes,especially Type 2 diabetes, hyperinsulinemia, metabolic syndrome X,dyslipidemia, and hypercholesterolemia; for treating cardiovasculardiseases including vascular disease, atherosclerosis, coronary heartdisease, cerebrovascular disease, heart failure and peripheral vesseldisease in a subject; for treating cancers including colon, skin, andlung cancers in a subject; for treating inflammatory diseases, includingasthma, rheumatoid arthritis, osteoarthritis, disorders associated withoxidative stress, inflammatory response to tissue injury, psoriasis,ulcerative colitis, dermatitis, and autoimmune disease in a subject; andfor treating polycystic ovary syndrome, climacteric, pathogenesis ofemphysema, ischemia-associated organ injury, doxorubicin-induced cardiacinjury, drug-induced hepatotoxicity, hypertoxic lung injury, scarring,wound healing, anorexia nervosa and bulimia nervosa in a subject, allcomprising the administration of a therapeutic amount of a compound ofFormula I. Preferably, the PPAR may be selected from the groupconsisting of PPARα, PPARδ, and PPARγ. More preferably, the PPAR isPPARδ.

In yet another aspect, the invention further discloses compounds ofFormula I or pharmaceutical compositions thereof for use in themanufacture of a medicament for the prevention or treatment of a diseaseor condition ameliorated by the modulation of a PPAR. The invention alsodiscloses the use of a compound of Formula I according to the inventionfor the manufacture of a medicament: for raising HDL, lowering LDLc,shifting LDL particle size from small dense to normal LDL, or inhibitingcholesterol absorption in a subject; for decreasing insulin resistanceor lowering blood pressure in a subject; for treating obesity, diabetes,especially Type 2 diabetes, hyperinsulinemia, metabolic syndrome X,dyslipidemia, and hypercholesterolemia; for treating cardiovasculardiseases including vascular disease, atherosclerosis, coronary heartdisease, cerebrovascular disease, heart failure and peripheral vesseldisease in a subject; for treating cancers including colon, skin, andlung cancers in a subject; for treating inflammatory diseases, includingasthma, rheumatoid arthritis, osteoarthritis, disorders associated withoxidative stress, inflammatory response to tissue injury, psoriasis,ulcerative colitis, dermatitis, and autoimmune disease in a subject; andfor treating polycystic ovary syndrome, climacteric, pathogenesis ofemphysema, ischemia-associated organ injury, doxorubicin-induced cardiacinjury, drug-induced hepatotoxicity, hypertoxic lung injury, scarring,wound healing, anorexia nervosa and bulimia nervosa in a subject, allcomprising the administration of a therapeutic amount of a compound ofFormula I. Preferably, the PPAR may be selected from the groupconsisting of PPARα, PPARδ, and PPARγ. More preferably, the PPAR isPPARδ.

In yet another aspect, the present invention provides for compounds ofFormula I or pharmaceutical compositions thereof for use in thetreatment of a disease or condition ameliorated by the modulation of aPPAR. Such PPAR-mediated diseases and conditions may be selected withoutlimitation from those listed in the preceding paragraphs. Preferably,the PPAR may be selected from the group consisting of PPARα, PPARδ, andPPARγ. More preferably, the PPAR is PPARδ.

Another aspect of the invention are compounds of Formula I,pharmaceutically acceptable prodrugs, pharmaceutically activemetabolites, or pharmaceutically acceptable salts thereof having an EC₅₀value less than 5 μM against PPAR as measured by functional cell assay.Preferably, said compounds have EC₅₀ values less than 5 μM againstPPARδ.

Another aspect of the invention are compounds which modulate aperoxisome proliferator-activated receptor (PPAR) function, wherein saidPPAR is selected from the group consisting of PPARα, PPARδ, and PPARγ.Preferably, said modulation is selective for PPARδ over the otherisoforms. More preferably, said modulation is 100-fold selective orgreater for PPARδ. Most preferably, said modulation is 200-500 foldselective for PPARδ.

As used in the present specification the following terms have themeanings indicated:

The term “acyl,” as used herein, alone or in combination, refers to acarbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,heterocycle, or any other moiety were the atom attached to the carbonylis carbon. An “acetyl” group refers to a —C(O)CH₃, group.

The term “acylamino” embraces an amino radical substituted with an acylgroup. An example of an “acylamino” radical is acetylamino (CH₃C(O)NH—).

The term “alkenyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon radical having one or moredouble bonds and containing from 2 to 20 carbon atoms. Alkenylene refersto a carbon-carbon double bond system attached at two or more positionssuch as ethenylene [(—CH═CH—),(—C::C—)]. Examples of suitable alkenylradicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl andthe like.

The term “alkoxy,” as used herein, alone or in combination, refers to analkyl ether radical wherein the term alkyl is as defined above. Examplesof suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, ethoxyethoxy,methoxypropoxyethoxy, ethoxypentoxyethoxyethoxy and the like.

The term “alkoxyalkoxy,” as used herein, alone or in combination, refersto an alkoxy group attached to the parent molecular moiety throughanother alkoxy group.

The term “alkoxyalkyl,” as used herein, alone or in combination, refersto an alkoxy group attached to the parent molecular moiety through analkyl group.

The term “alkoxycarbonyl,” as used herein, alone or in combination,refers to an alkoxy group attached to the parent molecular moietythrough a carbonyl group.

The term “alkyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl radical containing from 1 to andincluding 20 carbon atoms. Alkyl, alone or in combination, refers to analkyl radical which is optionally substituted as defined herein.Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl,octyl, noyl and the like.

The term “alkylamino,” as used herein, alone or in combination, refersto an amino group attached to the parent molecular moiety through analkyl group.

The term “alkylcarbonyl” and “alkanoyl,” as used herein, alone or incombination, refers to an alkyl group attached to the parent molecularmoiety through a carbonyl group. Examples of such groups includemethylcarbonyl and ethylcarbonyl.

The term “alkylene,” as used herein, alone or in combination, refers toa saturated aliphatic group derived from a straight or branched chainsaturated hydrocarbon attached at two or more positions, such asmethylene (—CH₂—).

The term “alkylidene,” as used herein, alone or in combination, refersto an alkenyl group in which one carbon atom of the carbon-carbon doublebond belongs to the moiety to which the alkenyl group is attached.

The term “alkylsulfinyl,” as used herein, alone or in combination,refers to an alkyl group attached to the parent molecular moiety througha sulfinyl group.

The term “alkylsulfonyl,” as used herein, alone or in combination,refers to an alkyl group attached to the parent molecular moiety througha sulfonyl group.

The term “alkylthio,” as used herein, alone or in combination, refers toan alkyl thioether (R—S—) radical wherein the term alkyl is as definedabove. Examples of suitable alkyl thioether radicals include methylthio,ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio,sec-butylthio, tert-butylthio, ethoxyethylthio, methoxypropoxyethylthio,ethoxypentoxyethoxyethylthio and the like.

The term “alkynyl,” alone or in combination, alone or in combination,refers to a straight-chain or branched chain hydrocarbon radical havingone or more triple bonds and containing preferably from 2 to 20 carbonatoms. Alkynylene refers to a carbon-carbon triple bond attached at twopositions such as ethynylene (—C:::C—, —C≡C—). Examples of alkynylradicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl,butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl,3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl,3,3-dimethylbutyn-1-yl, and the like.

The term “amido,” as used herein, alone or in combination, refers to anamino group as described below attached to the parent molecular moietythrough a carbonyl group. The term “C-amido” as used herein, alone or incombination, refers to a —C(═O)—NR₂ group with R as defined herein. Theterm “N-amido” as used herein, alone or in combination, refers to aRC(═O)NH— group, with R as defined herein.

The term “amino,” as used herein, alone or in combination, refers to—NRR′, wherein R and R′ are independently selected from the groupconsisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,alkyl, alkylcarbonyl, aryl, arylalkenyl, arylalkyl, cycloalkyl,haloalkylcarbonyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl,heterocycle, heterocycloalkenyl, and heterocycloalkyl, wherein the aryl,the aryl part of the arylalkenyl, the arylalkyl, the heteroaryl, theheteroaryl part of the heteroarylalkenyl and the heteroarylalkyl, theheterocycle, and the heterocycle part of the heterocycloalkenyl and theheterocycloalkyl can be optionally substituted with one, two, three,four, or five substituents independently selected from the groupconsisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halo,haloalkoxy, haloalkyl, hydroxy, hydroxy-alkyl, nitro, and oxo.

The term “aminoalkyl,” as used herein, alone or in combination, refersto an amino group attached to the parent molecular moiety through analkyl group.

The terms “aminocarbonyl” and “carbamoyl,” as used herein, alone or incombination, refer to an amino-substituted carbonyl group, wherein theamino group can be a primary or secondary amino group containingsubstituents selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl radicals and the like.

The term “aralkenyl” or “arylalkenyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkenyl group.

The term “aralkoxy” or “arylalkoxy,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkoxy group.

The term “aralkyl” or “arylalkyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term “aralkylamino” or “arylalkylamino,” as used herein, alone or incombination, refers to an arylalkyl group attached to the parentmolecular moiety through a nitrogen atom, wherein the nitrogen atom issubstituted with hydrogen.

The term “aralkylidene” or “arylalkylidene,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkylidene group

The term “aralkylthio” or “arylalkylthio,” as used herein, alone or incombination, refers to an arylalkyl group attached to the parentmolecular moiety through a sulfur atom.

The term “aralkynyl” or “arylalkynyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkynyl group.

The term “aralkoxycarbonyl,” as used herein, alone or in combination,refers to a radical of the formula aralkyl-O—C(O)— in which the term“aralkyl,” has the significance given above. Examples of anaralkoxycarbonyl radical are benzyloxycarbonyl (Z or Cbz) and4-methoxyphenylmethoxycarbonyl (MOS).

The term “aralkanoyl,” as used herein, alone or in combination, refersto an acyl radical derived from an aryl-substituted alkanecarboxylicacid such as benzoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl),4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl,4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl, and the like. The term“aroyl” refers to an acyl radical derived from an arylcarboxylic acid,“aryl” having the meaning given below. Examples of such aroyl radicalsinclude substituted and unsubstituted benzoyl or napthoyl such asbenzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl,4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl,6-carboxy-2-naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl,3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl,3-(benzyloxyformamido)-2-naphthoyl, and the like.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendent manner or may be fused. The term “aryl”embraces aromatic radicals such as benzyl, phenyl, naphthyl,anthracenyl, phenanthryl, indanyl, indenyl, annulenyl, azulenyl,tetrahydronaphthyl, and biphenyl.

The terms “arylcarbonyl” and “aroyl,” as used herein, alone or incombination, refer to an aryl group attached to the parent molecularmoiety through a carbonyl group.

The term “aryloxy,” as used herein, alone or in combination, refers toan aryl group attached to the parent molecular moiety through an oxygenatom.

The term “arylsulfonyl,” as used herein, alone or in combination, refersto an aryl group attached to the parent molecular moiety through asulfonyl group.

The term “arylthio,” as used herein, alone or in combination, refers toan aryl group attached to the parent molecular moiety through a sulfuratom.

The terms “benzo” and “benz,” as used herein, alone or in combination,refer to the divalent radical C₆H₄=derived from benzene. Examplesinclude benzothiophene and benzimidazole.

The term “O-carbamyl” as used herein, alone or in combination, refers toa —OC(O)NR, group-with R as defined herein.

The term “N-carbamyl” as used herein, alone or in combination, refers toa ROC(O)NH— group, with R as defined herein.

The term “carbonyl,” as used herein, when alone includes formyl [—C(O)H]and in combination is a —C(O)— group.

The term “carboxy,” as used herein, refers to —C(O)OH or thecorresponding “carboxylate” anion, such as is in a carboxylic acid salt.An “O-carboxy” group refers to a RC(O)O— group, where R is as definedherein. A “C-carboxy” group refers to a —C(O)OR groups where R is asdefined herein.

The term “cyano,” as used herein, alone or in combination, refers to—CN.

The term “cycloalkyl,” as used herein, alone or in combination, refersto a saturated or partially saturated monocyclic, bicyclic or tricyclicalkyl radical wherein each cyclic moiety contains from 3 to 12,preferably five to seven, carbon atom ring members and which mayoptionally be a benzo fused ring system which is optionally substitutedas defined herein. Examples of such cycloalkyl radicals includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and the like.“Bicyclic” and “tricyclic” as used herein are intended to include bothfused ring systems, such as decahydronapthalene, octahydronapthalene aswell as the multicyclic (multicentered) saturated or partiallyunsaturated type. The latter type of isomer is exemplified in general bybicyclo[2,2,2]octane, bicyclo[2,2,2]octane, bicyclo[1,1,1]pentane,camphor and bicyclo[3,2,1]octane.

The term “cycloalkylalkyl,” as used herein, alone or in combination,refers to an alkyl radical as defined above which is substituted by acycloalkyl radical as defined above. Examples of such cycloalkylalkylradicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl,2-cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl,cyclopentylpropyl, cyclohexylbutyl and the like.

The term “cycloalkylcarbonyl,” as used herein, alone or in combination,refers to an acyl radical of the formula cycloalkyl-(C═O)— in which theterm “cycloalkyl” has the significance give above, such ascyclopropylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl,1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl,1-hydroxy-1,2,3,4-tetrahydro-6-naphthoyl and the like.

The term “ester,” as used herein, alone or in combination, refers to analkoxy, aryloxy, cycloalkoxy, heteroaryloxy, and heterocyclooxy attachedto a carbonyl group.

The term “ether,” as used herein, alone or in combination, refers to anoxy group bridging two moieties linked at carbon atoms.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to F, Cl, Br, or I.

The term “haloalkoxy,” as used herein, alone or in combination, refersto a haloalkyl group attached to the parent molecular moiety through anoxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers toan alkyl radical having the meaning as defined above wherein one or morehydrogens are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkylradical, for one example, may have either an iodo, bromo, chloro orfluoro atom within the radical. Dihalo and polyhaloalkyl radicals mayhave two or more of the same halo atoms or a combination of differenthalo radicals. Examples of haloalkyl radicals include fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. “Haloalkylene” refersto a halohydrocarbyl group attached at two or more positions. Examplesinclude fluoromethylene (—CFH—), difluoromethylene (—CF₂—),chloromethylene (—CHCl—) and the like. Examples of such haloalkylradicals include chloromethyl, 1-bromoethyl, fluoromethyl,difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, perfluorodecyland the like.

The term “haloalkylcarbonyl,” as used herein, alone or in combination,refers to a haloalkyl group attached to the parent molecular moietythrough a carbonyl group.

The term “heteroalkyl,” as used herein, alone or in combination, refersto a stable straight or branched chain, or cyclic hydrocarbon radical,or combinations thereof, fully saturated or containing from 1 to 3degrees of unsaturation, consisting of the stated number of carbon atomsand from one to three heteroatoms selected from the group consisting ofO, N, and S, and wherein the nitrogen and sulfur atoms may optionally beoxidized and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N and S may be placed at any interior position of theheteroalkyl group. Up to two heteroatoms may be consecutive, such as,for example, —CH2-NH—OCH3.

The term “heteroaryl” embraces unsaturated heterocyclic radicals. Suchunsaturated heterocyclic radicals, also termed “heteroaryl” radicals,refer to 3 to 7 membered, preferably 5 to 7 membered, rings wherein atleast one atom is selected from the group consisting of O, S, and N.Heteroaryl groups are exemplified by: unsaturated 3 to 7 memberedheteromonocyclic groups containing 1 to 4 nitrogen atoms, for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.]tetrazolyl [e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensedheterocyclic group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo[1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-memberedheteromonocyclic groups containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupscontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl[e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,etc.]etc.; unsaturated condensed heterocyclic groups containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl,benzoxadiazolyl, etc.]; unsaturated 3 to 6-membered heteromonocyclicgroups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, forexample, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] and isothiazolyl;unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atomsand 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl,etc.] and the like. The term also embraces radicals where heterocyclicradicals are fused with aryl radicals. Examples of such fused bicyclicradicals include benzofuryl, benzothienyl, and the like.

The term “heteroarylalkenyl,” as used herein, alone or in combination,refers to a heteroaryl group attached to the parent molecular moietythrough an alkenyl group.

The term “heteroarylalkoxy,” as used herein, alone or in combination,refers to a heteroaryl group attached to the parent molecular moietythrough an alkoxy group.

The term “heteroarylalkyl,” as used herein, alone or in combination,refers to a heteroaryl group attached to the parent molecular moietythrough an alkyl group.

The term “heteroarylalkylidene,” as used herein, alone or incombination, refers to a heteroaryl group attached to the parentmolecular moiety through an alkylidene group.

The term “heteroaryloxy,” as used herein, alone or in combination,refers to a heteroaryl group attached to the parent molecular moietythrough an oxygen atom.

The term “heteroarylsulfonyl,” as used herein, alone or in combination,refers to a heteroaryl group attached to the parent molecular moietythrough a sulfonyl group.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” asused herein, alone or in combination, each refer to a saturated,partially unsaturated, or fully unsaturated monocyclic, bicyclic, ortricyclic heterocyclic radical containing at least one, preferably 1 to4, and more preferably 1 to 2 heteroatoms as ring members, wherein eachsaid heteroatom may be independently selected from the group consistingof nitrogen, oxygen, and sulfur, and wherein there are preferably 3 to 8ring members in each ring, more preferably 3 to 7 ring members in eachring, and most preferably 5 to 6 ring members in each ring.“Heterocycloalkyl” and “heterocycle” are intended to include sulfones,sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclicfused and benzo fused ring systems; additionally, both terms alsoinclude systems where a heterocycle ring is fused to an aryl group, asdefined herein, or an additional heterocycle group. Heterocycle groupsof the invention are exemplified by aziridinyl, azetidinyl,1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl,dihydrocinnolinyl, dihydrobenzodioxinyl,dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl,dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl,isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl,tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. Theheterocycle groups may be optionally substituted unless specificallyprohibited.

The term “heterocycloalkenyl,” as used herein, alone or in combination,refers to a heterocycle group attached to the parent molecular moietythrough an alkenyl group.

The term “heterocycloalkoxy,” as used herein, alone or in combination,refers to a heterocycle group attached to the parent molecular groupthrough an oxygen atom.

The term “heterocycloalkyl,” as used herein, alone or in combination,refers to an alkyl radical as defined above in which at least onehydrogen atom is replaced by a heterocyclo radical as defined above,such as pyrrolidinylmethyl, tetrahydrothienylmethyl, pyridylmethyl andthe like.

The term “heterocycloalkylidene,” as used herein, alone or incombination, refers to a heterocycle group attached to the parentmolecular moiety through an alkylidene group.

The term “hydrazinyl” as used herein, alone or in combination, refers totwo amino groups joined by a single bond, i.e., —N—N—.

The term “hydroxy,” as used herein, alone or in combination, refers toOH,

The term “hydroxyalkyl,” as used herein, alone or in combination, refersto a hydroxy group attached to the parent molecular moiety through analkyl group.

The term “imino,” as used herein, alone or in combination, refers to═N—.

The term “iminohydroxy,” as used herein, alone or in combination, refersto ═N(OH) and ═N—O—.

The phrase “in the main chain” refers to the longest contiguous oradjacent chain of carbon atoms starting at the point of attachment of agroup to the compounds of this invention.

The term “isocyanato” refers to a —NCO group.

The term “isothiocyanato” refers to a —NCS group.

The phrase “linear chain of atoms” refers to the longest straight chainof atoms independently selected from carbon, nitrogen, oxygen andsulfur.

The term “lower,” as used herein, alone or in combination, meanscontaining from 1 to and including 6 carbon atoms.

The term “mercaptoalkyl” refers to a R′SR— group, where R and R′ are asdefined herein.

The term “mercaptomercaptyl” refers to a RSR′S— group, where R is asdefined herein.

The term “mercaptyl” refers to a RS— group, where R is as definedherein.

The term “null” refers to a lone electron pair.

The term “nitro,” as used herein, alone or in combination, refers to—NO₂.

The terms “oxy” or “oxa,” as used herein, alone or in combination, referto —O—

The term “oxo,” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” refers to an alkyl group where all of thehydrogen atoms are replaced by halogen atoms.

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein,alone or in combination, refer the —SO₃H group and its anion as thesulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to—S and —S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to—S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to—SO₂—.

The term “N-sulfonamido” refers to a RS(═O)₂NH— group with R as definedherein.

The term “S-sulfonamido” refers to a —S(═O)₂NR₂, group, with R asdefined herein.

The terms “thia” and “thio,” as used herein, alone or in combination,refer to a —S— group or an ether wherein the oxygen is replaced withsulfur. The oxidized derivatives of the thio group, namely sulfinyl andsulfonyl, are included in the definition of thia and thio.

The term “thioether,” as used herein, alone or in combination, refers toa thio group bridging two moieties linked at carbon atoms.

The term “thiol,” as used herein, alone or in combination, refers to an—SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl[—(C═S)—H] and in combination is a —C═S— group.

The term “N-thiocarbamyl” refers to an ROC(═S)NH— group, with R asdefined herein.

The term “O-thiocarbamyl” refers to a —OC(═S)—NR, group with R asdefined herein.

The term “thiocyanato” refers to a —CNS group.

The term “trihalomethanesulfonamido” refers to a X₃CS(═O)₂NR— group withX is a halogen and R as defined herein.

The term “trihalomethanesulfonyl” refers to a X₃CS(═O)₂— group where Xis a halogen.

The term “trihalomethoxy” refers to a X₃CO— group where X is a halogen.

The term “trisubstituted silyl,” as used herein, alone or incombination, refers to a silicone group substituted at its three freevalences with groups as listed herein under the definition ofsubstituted amino. Examples include trimethysilyl,tert-butyldimethylsilyl, triphenylsilyl and the like.

Asymmetric centers exist in the compounds of the present invention.These centers are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the invention encompasses all stereochemical isomericforms, including diastereomeric, enantiomeric, and epimeric forms, ormixtures thereof. Individual stereoisomers of compounds can be preparedsynthetically from commercially available starting materials whichcontain chiral centers or by preparation of mixtures of enantiomericproducts followed by separation such as conversion to a mixture ofdiastereomers followed by separation or recrystallization,chromatographic techniques, direct separation of enantiomers on chiralchromatographic columns, or any other appropriate method known in theart. Starting compounds of particular stereochemistry are eithercommercially available or can be made and resolved by techniques knownin the art. Additionally, the compounds of the present invention mayexist as geometric isomers. The present invention includes all cis,trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as theappropriate mixtures thereof. Additionally, compounds may exist astautomers; all tautomeric isomers are provided by this invention.Additionally, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups ordesignated subsets thereof, alone or in combination: lower alkyl, loweralkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lowerheterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl,lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl,aryloxy, lower haloalkoxy, oxo, lower alkoxy, lower acyloxy, carbonyl,carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido,cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino,amido, nitro, thiol, lower alkylthio, arylthio, lower alkylsulfinyl,lower alkylsulfonyl, arylsulfinyl, arylsulfonyl, arylthio, sulfonate,sulfonic acid, trisubstituted silyl, N₃, NHCH₃, N(CH₃)₂, SH, SCH₃,C(O)CH₃, CO₂CH₃, CO₂H, C(O)NH₂, pyridinyl, thiophene, furanyl, lowercarbamate, and lower urea. An optionally substituted group may beunsubstituted (e.g., —CH₂CH₃), fully substituted (e.g., —CF₂CF₃),monosubstituted (e.g., —CH₂CH₂F) or substituted at a level anywherein-between fully substituted and monosubstituted (e.g., —CH₂CF₃). Wheresubstituents are recited without qualification as to substitution, bothsubstituted and unsubstituted forms are encompassed. Where a substituentis qualified as “substituted,” the substituted form is specificallyintended.

The term R or the term R′, appearing by itself and without a numberdesignation, unless otherwise defined, refers to an optionallysubstituted moiety selected from the group consisting of alkyl,cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl. Such Rand R′ groups should be understood to be optionally substituted asdefined herein. Whether an R group has a number designation or not,every R group, including R, R′ and R^(n) where n=(1, 2, 3, . . . n),every substituent, and every term should be understood to be independentof every other in terms of selection from a group. Should any variable,substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more thanone time in a formula or generic structure, its definition at eachoccurrence is independent of the definition at every other occurrence.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered to be part oflarger substructure. A bond may be single, double, or triple unlessotherwise specified.

In the event that G₃ is designated to be “a bond”, the structure shownbelow (right side) is intended: the entity designated G₃ collapses to asingle bond connecting G₂ and G₄:

Similarly, when, within G₁, n is 0 or both r and s are 0, G₁ collapsesto a bond connecting A and T.

The compounds of the present invention can exist as therapeuticallyacceptable salts.

The term “therapeutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds of the present inventionwhich are water or oil-soluble or dispersible, which are suitable fortreatment of diseases without undue toxicity, irritation, andallergic-response; which are commensurate with a reasonable benefit/riskratio, and which are effective for their intended use. The salts can beprepared during the final isolation and purification of the compounds orseparately by reacting a basic group with a suitable acid.Representative acid addition salts include acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate),lactate, male-ate, mesitylenesulfonate, methanesulfonate,naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate,propionate, succinate, tartrate, trichloroacetate, trifluoroacetate,phosphate, glutamate, bicarbonate, para-toluenesulfonate, andundecanoate. Also, basic groups in the compounds of the presentinvention can be quaternized with methyl, ethyl, propyl, and butylchlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamylsulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, andiodides; and benzyl and phenethyl bromides. Examples of acids which canbe employed to form therapeutically acceptable addition salts includeinorganic acids such as hydrochloric, hydrobromic, sulfuric, andphosphoric, and organic acids such as oxalic, maleic, succinic, andcitric.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

The term “prodrug” refers to a compound that is made more active invivo. The present compounds can also exist as prodrugs. Prodrugs of thecompounds described herein are structurally modified forms of thecompound that readily undergo chemical changes under physiologicalconditions to provide the compound. Additionally, prodrugs can beconverted to the compound by chemical or biochemical methods in an exvivo environment. For example, prodrugs can be slowly converted to acompound when placed in a transdermal patch reservoir with a suitableenzyme or chemical reagent. Prodrugs are often useful because, in somesituations, they may be easier to administer than the compound, orparent drug. They may, for instance, be bioavailable by oraladministration whereas the parent drug is not. The prodrug may also haveimproved solubility in pharmaceutical compositions over the parent drug.A wide variety of prodrug derivatives are known in the art, such asthose that rely on hydrolytic cleavage or oxidative activation of theprodrug. An example, without limitation, of a prodrug would be acompound which is administered as an ester (the “prodrug”), but then ismetabolically hydrolyzed to the carboxylic acid, the active entity.Additional examples include peptidyl derivatives of a compound. The term“therapeutically acceptable prodrug,” refers to those prodrugs orzwitterions which are suitable for use in contact with the tissues ofpatients without undue toxicity, irritation, and allergic response, arecommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use.

The term “activate” refers to increasing the cellular function of aPPAR.

The term “inhibit” refers to decreasing the cellular function of a PPAR.The PPAR function may be the interaction with a natural binding partneror catalytic activity.

The term “modulate” refers to the ability of a compound of the inventionto alter the function of a PPAR. A modulator may activate the activityof a PPAR. The term “modulate” also refers to altering the function of aPPAR by increasing or decreasing the probability that a complex formsbetween a PPAR and a natural binding partner. A modulator may increasethe probability that such a complex forms between the PPAR and thenatural binding partner, may increase or decrease the probability that acomplex forms between the PPAR and the natural binding partner dependingon the concentration of the compound exposed to the PPAR, and or maydecrease the probability that a complex forms between the PPAR and thenatural binding partner.

As used herein, reference to “treatment” of a patient is intended toinclude prophylaxis. The term “patient” means all mammals includinghumans. Examples of patients include humans, cows, dogs, cats, goats,sheep, pigs, and rabbits.

The term “therapeutically effective amount” as used herein refers tothat amount of the compound being administered which will relieve tosome extent one or more of the symptoms of the disease, condition ordisorder being treated. In reference to the treatment of diabetes ordyslipidemia a therapeutically effective amount may refer to that amountwhich has the effect of (1) reducing the blood glucose levels; (2)normalizing lipids, e.g. triglycerides, low-density lipoprotein; (3)relieving to some extent (or, preferably, eliminating) one or moresymptoms associated with the disease, condition or disorder to betreated; and/or (4) raising HDL.

The terms “enhance” or “enhancing” means to increase or prolong eitherin potency or duration a desired effect. Thus, in regard to enhancingthe effect of therapeutic agents, the term “enhancing” refers to theability to increase or prolong, either in potency or duration, theeffect of other therapeutic agents on a system. An “enhancing-effectiveamount,” as used herein, refers to an amount adequate to enhance theeffect of another therapeutic agent in a desired system. When used in apatient, amounts effective for this use will depend on the severity andcourse of the disease, disorder or condition (including, but not limitedto, metabolic disorders), previous therapy, the patient's health statusand response to the drugs, and the judgment of the treating physician.It is considered well within the skill of the art for one to determinesuch enhancing-effective amounts by routine experimentation.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic condition or disorderdescribed in the present disclosure. Such administration encompassesco-administration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofactive ingredients or in multiple, separate capsules for each activeingredient. In addition, such administration also encompasses use ofeach type of therapeutic agent in a sequential manner. In either case,the treatment regimen will provide beneficial effects of the drugcombination in treating the conditions or disorders described herein.

In another aspect, the present invention relates to a method of treatinga disease comprising identifying a patient in need thereof, andadministering a therapeutically effective amount of a compound ofFormula I, as described herein, to the patient.

The compounds of the invention are useful in the treatment of a diseaseor condition ameliorated by the modulation of an PPAR-delta. Specificdiseases and conditions modulated by PPAR-delta and for which thecompounds and compositions are useful include but are not limited todyslipidemia, syndrome X, heart failure, hypercholesteremia,cardiovascular disease, type II diabetes mellitus, type 1 diabetes,insulin resistance hyperlipidemia, obesity, anorexia bulimia,inflammation and anorexia nervosa. Other indications include reductionof scarring and wound healing.

The compounds of the invention may also be used (a) for raising HDL in asubject; (b) for treating Type 2 diabetes, decreasing insulin resistanceor lowering blood pressure in a subject; (c) for decreasing LDLc in asubject; (d) for shifting LDL particle size from small dense to normaldense LDL in a subject; (e) for reducing cholesterol absorption orincreasing cholesterol excretion in a subject; (f) for reducing theexpression of NPC1L1 in a subject; (g) for treating atheroscleroticdiseases including vascular disease, coronary heart disease,cerebrovascular disease and peripheral vessel disease in a subject; and(h) for treating inflammatory diseases, including asthma, rheumatoidarthritis, osteoarthritis, disorders associated with oxidative stress,inflammatory response to tissue injury, psoriasis, ulcerative colitis,dermatitis, and autoimmune disease in a subject.

The compounds of the invention may also be used for treating,ameliorating, or preventing a disease or condition selected from thegroup consisting of obesity, diabetes, hyperinsulinemia, metabolicsyndrome X, polycystic ovary syndrome, climacteric, disorders associatedwith oxidative stress, inflammatory response to tissue injury,pathogenesis of emphysema, ischemia-associated organ injury,doxorubicin-induced cardiac injury, drug-induced hepatotoxicity,atherosclerosis, and hypertoxic lung injury.

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease, condition or disorder mediated,modulated or involving the PPARs, including but not limited to metabolicdiseases, conditions, or disorders, as described above, in an amountsufficient to cure or at least partially arrest the symptoms of thedisease, disorder or condition. Amounts effective for this use willdepend on the severity and course of the disease, disorder or condition,previous therapy, the patient's health status and response to the drugs,and the judgment of the treating physician. It is considered well withinthe skill of the art for one to determine such therapeutically effectiveamounts by routine experimentation (e.g., a dose escalation clinicaltrial).

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or conditionmediated, modulated or involving the PPARs, including but not limited tometabolic diseases, conditions, or disorders, as described above. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. It is considered well within theskill of the art for one to determine such prophylactically effectiveamounts by routine experimentation (e.g., a dose escalation clinicaltrial).

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. When the symptoms have been alleviated to thedesired level, treatment can cease. Patients can, however, requireintermittent treatment on a long-term basis upon any recurrence ofsymptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be routinelydetermined in a manner known in the art according to the particularcircumstances surrounding the case, including, e.g., the specific agentbeing administered, the route of administration, the condition beingtreated, and the subject or host being treated. In general, however,doses employed for adult human treatment will typically be in the rangeof 0.02-5000 mg per day, preferably 1-1500 mg per day. The desired dosemay conveniently be presented in a single dose or as divided dosesadministered at appropriate intervals, for example as two, three, fouror more sub-doses per day.

In certain instances, it may be appropriate to administer at least oneof the compounds described herein (or a pharmaceutically acceptablesalt, ester, amide, prodrug, or solvate) in combination with anothertherapeutic agent. By way of example only, if one of the side effectsexperienced by a patient upon receiving one of the compounds herein ishypertension, then it may be appropriate to administer ananti-hypertensive agent in combination with the initial therapeuticagent. Or, by way of example only, the therapeutic effectiveness of oneof the compounds described herein may be enhanced by administration ofan adjuvant (i.e., by itself the adjuvant may only have minimaltherapeutic benefit, but in combination with another therapeutic agent,the overall therapeutic benefit to the patient is enhanced). Or, by wayof example only, the benefit of experienced by a patient may beincreased by administering one of the compounds described herein withanother therapeutic agent (which also includes a therapeutic regimen)that also has therapeutic benefit. By way of example only, in atreatment for diabetes involving administration of one of the compoundsdescribed herein, increased therapeutic benefit may result by alsoproviding the patient with another therapeutic agent for diabetes. Inany case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient may simply beadditive of the two therapeutic agents or the patient may experience asynergistic benefit.

Specific, non-limiting examples of possible combination therapiesinclude use of the compound of formula (I) with: (a) statin and/or otherlipid lowering drugs for example MTP inhibitors and LDLR upregulators;(b) antidiabetic agents, e.g. metformin, sulfonylureas, or PPAR-gamma,PPAR-alpha and PPAR-alpha/gamma modulators (for examplethiazolidinediones such as e.g. Pioglitazone and Rosiglitazone); and (c)antihypertensive agents such as angiotensin antagonists, e.g.,telmisartan, calcium channel antagonists, e.g. lacidipine and ACEinhibitors, e.g., enalapril.

In any case, the multiple therapeutic agents (at least one of which is acompound of Formula I, described herein) may be administered in anyorder or even simultaneously. If simultaneously, the multipletherapeutic agents may be provided in a single, unified form, or inmultiple forms (by way of example only, either as a single pill or astwo separate pills). One of the therapeutic agents may be given inmultiple doses, or both may be given as multiple doses. If notsimultaneous, the timing between the multiple doses may be any durationof time ranging from a few minutes to four weeks.

While it may be possible for the compounds of the subject invention tobe administered as the raw chemical, it is also possible to present themas a pharmaceutical formulation. Accordingly, the subject inventionprovides a pharmaceutical formulation comprising a compound or apharmaceutically acceptable salt, ester, prodrug or solvate thereof,together with one or more pharmaceutically acceptable carriers thereofand optionally one or more other therapeutic ingredients. The carrier(s)must be “acceptable” in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof. Proper formulation is dependent upon the route ofadministration chosen. Any of the well-known techniques, carriers, andexcipients may be used as suitable and as understood in the art; e.g.,in Remington's Pharmaceutical Sciences. The pharmaceutical compositionsof the present invention may be manufactured in a manner that is itselfknown, e.g., by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orcompression processes.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, transmucosal, transdermal, rectaland topical (including dermal, buccal, sublingual, ophthalmic, andintraocular) administration although the most suitable route may dependupon for example the condition and disorder of the recipient. Theformulations may conveniently be presented in unit dosage form and maybe prepared by any of the methods well known in the art of pharmacy. Allmethods include the step of bringing into association a compound of thesubject invention or a pharmaceutically acceptable salt, ester, prodrugor solvate thereof (“active ingredient”) with the carrier whichconstitutes one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Alternately, one may administer the compound in a local rather thansystemic manner, for example, via injection of the compound directlyinto an organ, often in a depot or sustained release formulation.Furthermore, one may administer the drug in a targeted drug deliverysystem, for example, in a liposome coated with organ-specific antibody.The liposomes will be targeted to and taken up selectively by the organ.Topical formulations provided for local delivery include, but are notlimited to, gels, creams, ointments, sprays, salves, and patches.

For intravenous injections, the agents of the invention may beformulated in aqueous solutions, preferably in physiologicallycompatible buffers such as Hanks's solution, Ringer's solution, orphysiological saline buffer. For transmucosal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art. For other parenteralinjections, the agents of the invention may be formulated in aqueous ornonaqueous solutions, preferably with physiologically compatible buffersor excipients. Such excipients are generally known in the art.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carriersor excipients well known in the art. Such carriers enable the compoundsof the invention to be formulated as tablets, powders, pills, dragees,capsules, liquids, gels, syrups, elixirs, slurries, suspensions and thelike, for oral ingestion by a patient to be treated. Pharmaceuticalpreparations for oral use can be obtained by mixing one or more solidexcipient with one or more compound of the invention, optionallygrinding the resulting mixture, and processing the mixture of granules,after adding suitable auxiliaries, if desired, to obtain tablets ordragee cores. Suitable excipients are, in particular, fillers such assugars, including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as: for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methylcellulose,microcrystalline cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethyl cellulose; or others such as: polyvinylpyrrolidone (PVP orpovidone) or calcium phosphate. If desired, disintegrating agents may beadded, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. Dragee cores areprovided with suitable coatings. For this purpose, concentrated sugarsolutions may be used, which may optionally contain gum arabic, talc,polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/ortitanium dioxide, lacquer solutions, and suitable organic solvents orsolvent mixtures. Dyestuffs or pigments may be added to the tablets ordragee coatings for identification or to characterize differentcombinations of active compound doses. All formulations for oraladministration should be in dosages suitable for such administration.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, e.g., gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. The formulations may be presentedin unit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in powder form or in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, saline or sterile pyrogen-free water,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, polyethylene glycol, or otherglycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

One example of a pharmaceutical carrier for the hydrophobic compounds ofthe invention is a cosolvent system comprising benzyl alcohol, anonpolar surfactant, a water-miscible organic polymer, and an aqueousphase. The cosolvent system may be a 10% ethanol, 10% polyethyleneglycol 300, 10% polyethylene glycol 40 castor oil (PEG-40 castor oil)with 70% aqueous solution. This cosolvent system dissolves hydrophobiccompounds well, and itself produces low toxicity upon systemicadministration. Naturally, the proportions of a cosolvent system may bevaried considerably without destroying its solubility and toxicitycharacteristics. Furthermore, the identity of the cosolvent componentsmay be varied: for example, other low-toxicity nonpolar surfactants maybe used instead of PEG-40 castor oil, the fraction size of polyethyleneglycol 300 may be varied; other biocompatible polymers may replacepolyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars orpolysaccharides maybe included in the aqueous solution.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are well knownexamples of delivery vehicles or carriers for hydrophobic drugs. Certainorganic solvents such as N-methylpyrrolidone also may be employed,although usually at the cost of greater toxicity. Additionally, thecompounds may be delivered using a sustained-release system, such assemipermeable matrices of solid hydrophobic polymers containing thetherapeutic agent. Various sustained-release materials have beenestablished and are well known by those skilled in the art.Sustained-release capsules may, depending on their chemical nature,release the compounds for a few weeks up to over 100 days. Depending onthe chemical nature and the biological stability of the therapeuticreagent, additional strategies for protein stabilization may beemployed.

Besides being useful for human treatment, these compounds are alsouseful for veterinary treatment of companion animals, exotic animals andfarm animals, including mammals, rodents, and the like. More preferredanimals include horses, dogs, and cats.

Many of the compounds of the invention may be provided as salts withpharmaceutically compatible counterions. Acid addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include, but are not limited to: those derived from inorganicacids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like; as well as the salts derived fromrelatively nontoxic organic acids like acetic; propionic; isobutyric;lactic; maleic; malonic; benzoic; succinic; suberic; fumaric; mandelic;phthalic; benzenesulfonic; toluenesulfonic, including p-toluenesulfonic,m-toluenesulfonic, and o-toluenesulfonic; citric; tartaric;methanesulfonic; and the like. Also included are salts of amino acidssuch as arginate and the like, and salts of organic acids likeglucuronic or galactunoric acids and the like (see, for example, Bergeet al. J. Pharm. Sci. 66:1-19 (1977)). Salts tend to be more soluble inaqueous or other protonic solvents than are the corresponding free acidor base forms. Salts useful with the compounds of the present inventioninclude, without limitation, calcium, sodium, potassium, magnesium,hydrochloride, phosphate, sulfate, and p-toluenesulfonate salts. Thesalts can be prepared by contacting the compounds of the invention withan appropriate acid, either neat or in a suitable inert solvent, toyield the salt forms of the invention. In preferred embodiments, thep-toluenesulfonate (tosylate) is used with the disclosed compounds.

For example,4-[4-(4-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid prepared by any method can be contacted with a reagent selectedfrom the group consisting of calcium acetate, hydrochloric acid,phosphoric acid, sulfuric acid, sodium hydroxide, potassium hydroxide,magnesium acetate, and p-toluenesulfonic acid, preferably in a 1:1ratio, in a suitable solvent. Such solvents include but are not limitedto diisopropyl ether, toluene, dichloromethane, and acetonitrile. Anytechnique known in the art can be used to vary conditions to induceprecipitation or crystallization, including, without limitation:stirring for varying lengths of time at varying ambient conditions, theaddition of hexanes or diethyl ether, evaporation, and reduction oftemperature. In particular,4-[4-(4-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid can be contacted with p-toluenesulfonic acid to yield the tosylatesalt form of the invention, to form4-[4-(4-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid p-toluenesulfonate salt. The present invention provides for4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid p-toluenesulfonate salt. The present invention provides for4-[4-(4-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid p-toluenesulfonate salt. Additionally, the present inventionprovides for pharmaceutical compositions comprising a salt of a compoundof Formula I together with a pharmaceutically acceptable diluent orcarrier.

All references, patents or applications, U.S. or foreign, cited in theapplication are hereby incorporated by reference as if written herein.

The following schemes can be used to practice the present invention.

Various indane-carboxylic acids were prepared starting from theircorresponding indanyl-2-acetic acid, indan-2-carboxylic acid,indan-1-carboxylic acid or 6-methoxy indan-1-acetic acid ester headgroup. The indane was first chlorosulfonylated with neat chlorosulfonicacid. Sulfonamide formation was induced by reaction with the appropriatepiperazine or piperidine either at room temperature or at elevatedtemperatures when sterically hindered piperazines were used. Finally,base hydrolysis of the ester moiety was accomplished using lithiumhydroxide.

The methylated indan-carboxylic acids were synthesized in a similarmanner with the addition of an initial α-methylation using LHMDS andmethyl iodide (Scheme II).

Scheme III outlines the synthesis of indol-1-yl embodiments of thepresent invention. A 1-(2,3-dihydro-indol-1-yl)-ethanone was firstchlorosulfonylated using chlorosulfonic acid, followed by sulfonamideformation by reaction with the appropriate piperazine or piperidine. Theindole was then accessed by first removal of the acetyl protecting groupunder acidic conditions, followed by DDQ oxidation of the indoline. Theindole is then N-alkylated with methyl bromoacetate and furtherhydrolyzed with lithium hydroxide to provide the desired carboxylicacid.

The compounds in Scheme IV show a sulfonamide substituted at the6-position of the indole. Access to the 6-sulfonamide-5-bromo indolesbegins with chlorosulfonylation of1-(5-Bromo-2,3-dihydro-indol-1-yl)-ethanone, followed by sulfonamideformation with the appropriate piperazine or piperidine. The acetylprotecting group is then removed with conc. HCl in 1,4-dioxane, followedby DDQ oxidation yielding the indole head group. The indole isN-alkylated with methyl bromoacetate, followed by hydrolysis of theester with lithium hydroxide. In turn, the 6-sulfonamide-indoles can beaccessed by hydrogenation of the 5-bromo functionality before thehydrolysis step using catalytic hydrogenation with 10% Pd/C under ahydrogen atmosphere.

Scheme VI depicts a general method for coupling G₂-G₄ moieties tointermediate embodiments of the present invention and a general methodfor hydrolytically cleaving acid-protected intermediates to produceembodiments of the present invention.

Scheme VII depicts a general method for preparing 6-methoxybenzthiophene embodiments of the present invention.

Scheme VIII depicts a general method for preparing benzothiopheneembodiments of the present invention.

Several schemes present a general method for preparing a sulfonamidebond using a sulfonyl electrophile and a nitrogen nucleophile. In thisway, a wide variety of G₂-G₃-G₄ groups may be introduced in a modularway.

Scheme IX outlines the synthesis of various G₂-G₃-G₄ moieties startingfrom coupling the halogenated aryl G₄ groups with the appropriatepiperazine or piperidine. Sulfonamide formation was induced by reactionwith the chlorosulfonylated indane-carboxylic acid ester head groups(see Scheme I). Finally, base hydrolysis of the ester moiety wasaccomplished using lithium hydroxide.

The invention is further illustrated by the following examples.

EXAMPLE 1

{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-aceticacid

Step 1

{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-aceticacid methyl ester: Indanyl-2-acetic acid methyl ester (1.0 g, 5.26 mmol)was added to a stirring solution of chlorosulfonic acid (5 mL) at 0° C.The solution was stirred at 0° C. for 0.5 h, then room temperature for 3h. The resulting solution was poured slowly over ice and extracted withdiethyl ether (3×100 mL). The combined organic layers were dried(Na₂SO₄) and concentrated to afford a mixture of5-chlorosulfonyl-indan-2-acetic acid methyl ester and4-chlorosulfonyl-indan-2-acetic acid methyl ester (1.38 g, 4.78 mmol,91%). The sulfonyl chloride mixture was taken on to the next stepwithout further purification. The mixture of sulfonyl chlorides (370 mg,1.28 mmol) were dissolved in dry THF (10 mL). To this solution was added1-(4-trifluoromethylphenyl)piperazine (315 mg, 1.37 mmol), triethylamine(600 μL, 4.3 mmol) and DMAP (catalytic amount). The reaction was stirredat room temperature for 1 h, concentrated and directly purified bysilica gel flash column chromatography to separate the regioisomers (25%ethyl acetate in hexanes) affording{5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-aceticacid methyl ester (118 mg, 19%) and{4-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-aceticacid methyl ester (40 mg, 6%) as clear colorless oils.{5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-aceticacid methyl ester: ¹H NMR (400 MHz, CDCl₃)

7.57 (s, 1H), 7.56 (d, 1H), 7.45 (d, 2H), 7.33 (d, 1H), 6.87 (d, 2H),3.69 (s, 3H), 3.33 (m, 4H), 3.21 (dd, 2H), 3.14 (m, 4H), 2.95 (m, 1H),2.71 (dd, 2H), 2.52 (d, 2H).

Step 2

{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-aceticacid:{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-aceticacid methyl ester (118 mg, 0.245 mmol) was dissolved in THF (10 mL). Tothis solution was added 1M LiOH (5 mL) and was stirred at roomtemperature for 3 h. TLC indicated that the reaction was complete. Thereaction mixture was then quenched with Dowex 50WX4-50 until neutral andthen filtered to afford pure{5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-aceticacid (112 mg, 98%) as a white solid. The product can be further purifiedby silica gel flash column chromatography (dichloromethane/MeOH/AcOH95:5:0.1). ¹H NMR (400 MHz, MeOH-d₄)

7.60 (s, 1H), 7.56 (d, 1H), 7.45 (d, 2H), 7.41 (d, 1H), 7.00 (d, 2H),3.32 (m, 4H), 3.22 (m, 2H), 3.17 (m, 4H), 2.88 (m, 1H), 2.72 (m, 2H),2.47 (d, 2H); LCMS: 468.8 (M+1)⁺.

EXAMPLE 2

{4-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-aceticacid: The compound{4-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-aceticacid was synthesized according to the procedure from Example 1 using{4-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-aceticacid methyl ester from Example 1, Step 1. ¹H NMR (400 MHz, MeOH-d₄)

7.60 (d, 1H), 7.52 (d, 2H), 7.51 (d, 1H), 7.31 (t, 1H), 7.15 (d, 2H),3.53 (dd, 1H), 3.42 (m, 4H), 3.25 (m, 4H), 3.20 (m, 1H), 3.00 (dd, 1H),2.87 (m, 1H), 2.72 (m, 1H), 2.47 (m, 2H); LCMS: 468.8 (M+1)⁺.

EXAMPLE 3

{5-[4-(3,4-Dichlorophenyl)-piperazine-1-sulfonyl]-indan-2-yl}-aceticacid: The compound{5-[4-(3,4-dichlorophenyl)-piperazine-1-sulfonyl]-indan-2-yl}-aceticacid was synthesized according to the procedure from Example 1 using3,4-(dichlorophenyl)-piperazine. ¹H NMR (400 MHz, MeOH-d₄)

7.60 (s, 1H), 7.56 (d, 1H), 7.42 (d, 1H), 7.29 (d, 1H), 7.04 (d, 1H),6.83 (dd, 1H), 3.31 (m, 2H), 3.23 (m, 4H), 3.18 (m, 1H), 3.08 (m, 3H),2.90 (m, 1H), 2.74 (m, 2H), 2.46 (d, 2H); LCMS: 468.8 (M+1)⁺.

EXAMPLE 4

{4-[4-(3,4-Dichlorophenyl)-piperazine-1-sulfonyl]-indan-2-yl}-aceticacid: The compound{4-[4-(3,4-dichlorophenyl)-piperazine-1-sulfonyl]-indan-2-yl}-aceticacid was synthesized according to the procedure from Example 1 using3,4-(dichlorophenyl)-piperazine. ¹H NMR (400 MHz, MeOH-d₄)

7.59 (d, 1H), 7.52 (d, 1H), 7.38 (dd, 1H), 7.29 (d, 1H), 7.04 (d, 1H),6.85 (dd, 1H), 3.50 (dd, 1H), 3.20 (m, 8H), 2.98 (dd, 1H), 2.86 (m, 1H),2.72 (dd, 1H), 2.48 (m, 1H), 2.18 (m, 2H); LCMS: 468.9 (M+1)⁺.

EXAMPLE 5

5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure outlined in Example 1using indane-2-carboxylic acid methyl ester. ¹H NMR (400 MHz, MeOH-d₄)

7.64 (s, 1H), 7.60 (d, 1H), 7.46 (d, 2H), 7.46 (m, 1H), 7.01 (d, 2H),3.41 (m, 1H), 3.30 (m, 8H), 3.10 (m, 4H).

EXAMPLE 6

4-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound4-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure outlined in Example 1using indane-2-carboxylic acid methyl ester. ¹H NMR (400 MHz, MeOH-d₄)

7.63 (d, 1H), 7.53 (d, 1H), 7.46 (d, 2H), 7.40 (t, 1H), 7.03 (d, 2H),3.58-3.56 (m, 2H), 3.42-3.34 (m, 5H), 3.32-3.18 (m, 6H); LCMS: 455.0(M+1)⁺.

EXAMPLE 7

5-[4-(3,4-Dichlorophenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound5-[4-(3,4-dichlorophenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acidwas synthesized according to the procedure outlined in Example 1 usingindane-2-carboxylic acid methyl ester and3,4-(dichlorophenyl)-piperazine. ¹H NMR (400 MHz, MeOH-d₄)

7.61 (s, 1H), 7.56 (d, 1H), 7.42 (d, 1H), 7.28 (d, 1H), 7.03 (d, 1H),6.89 (dd, 1H), 3.30 (m, 1H), 3.28 (m, 4H), 3.32 (m, 4H), 3.08 (m, 4H).

EXAMPLE 8

4-[4-(3,4-Dichlorophenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound4-[4-(3,4-dichlorophenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acidwas synthesized according to the procedure outlined in Example 1 usingindane-2-carboxylic acid methyl ester and3,4-(dichlorophenyl)-piperazine. ¹H NMR (400 MHz, MeOH-d₄)

7.62 (d, 1H), 7.54 (d, 1H), 7.40 (t, 1H), 7.30 (d, 1H), 7.06 (d, 1H),6.86 (dd, 1H), 3.57-3.55 (m, 2H), 3.42-3.34 (m, 1H), 3.32-3.29 (m, 2H),3.26-3.16 (m, 8H); LCMS: 454.9 (M+1)⁺.

EXAMPLE 9

5-[4-(4-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound5-[4-(3,4-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure outlined in Example 1using indane-2-carboxylic acid methyl ester and1-[5-(trifluoromethyl)-pyrid-2-yl]-piperazine. ¹H NMR (400 MHz, MeOH-d₄)

8.01 (s, 1H), 7.69 (d, 1H), 7.61 (s, 1H), 7.56 (d, 1H), 7.41 (d, 1H),6.85 (d, 1H), 3.75 (m, 3H), 3.32 (m, 1H), 3.31 (m, 3H), 3.28 (m, 3H),3.05 (m, 3H); LCMS: 455.9 (M+1)⁺.

EXAMPLE 10

4-[4-(4-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound4-[4-(4-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure outlined in Example 1using indane-2-carboxylic acid methyl ester and1-[5-(trifluoromethyl)-pyrid-2-yl]-piperazine. ¹H NMR (400 MHz, MeOH-D₄)

8.35 (s, 1H), 7.74 (d, 1H), 7.65 (d, 1H), 7.55 (d, 1H), 7.42 (t, 1H),6.90 (d, 1H), 3.78 (m, 4H), 3.59 (d, 2H), 3.41 (m, 1H), 3.34 (m, 2H),3.20 (m, 4H); LCMS: 456.0 (M+1)⁺.

EXAMPLE 11

This single enantiomer of Example 10 was obtained by chiral HPLC(chiralpak ADH 0.46×15 cm Hex/IPA 94:6 (v/v) with 0.1% TFA, flow rate 1ml/min) separation from the racemate.

EXAMPLE 12

This single enantiomer of Example 10 was obtained by chiral HPLC(chiralpak ADH 0.46×15 cm Hex/IPA 94:6 (v/v) with 0.1% TFA, flow rate 1ml/min) separation from the racemate.

EXAMPLE 13

2-Methyl-5-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid

Step 1

2-Methyl-indan-2-carboxylic acid methyl ester: Indane-2-carboxylic acidmethyl ester (550 mg, 3.125 mmol) was dissolved in THF (20 mL). At −78°C. LiHMDS (1M solution in THF, 3.75 mL) was added into the reactionmixture. The solution was stirred for 15 min at −78° C., warmed to 0° C.for 15 min and then −78° C. for an additional 15 min. Methyl iodide (250μL, 4.01 mmol) was then added into the reaction mixture followed bystirring at −78° C. for 15 min, room temperature for 30 min and thenquenched with saturated ammonium chloride. The solution was then dilutedwith diethyl ether and washed with saturated sodium bicarbonate, brine,dried (MgSO₄), filtered and concentrated. The crude mixture was thenpurified by silica gel flash column chromatography to afford2-methyl-indan-2-carboxylic acid methyl ester (52 mg, 9%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃)

7.16 (m, 4H), 3.72 (t, 3H), 3.48 (d, 2H), 2.81 (d, 2H), 1.36 (s, 3H).

Step 2

2-Methyl-5-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound2-methyl-5-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure outlined in Example 1using 1-[5-(trifluoromethyl)-pyrid-2-yl]-piperazine and2-methyl-indan-2-carboxylic acid methyl ester to afford2-methyl-5-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid. ¹H NMR (400 MHz, MeOH-d₄)

8.30 (s, 1H), 7.70 (dd, 1H), 7.61 (s, 1H), 7.58 (d, 1H), 7.41 (d, 1H),6.86 (d, 1H), 3.74 (s, 4H), 3.50 (dd, 2H), 3.06 (m, 4H), 2.90 (dd, 2H),1.35 (s, 3H); LCMS: 470.5 (M+1)⁺.

EXAMPLE 14

2-Methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure outlined in Example 13.¹H NMR (400 MHz, MeOH-d₄)

8.32 (s, 1H), 7.74 (dd, 1H), 7.61 (d, 1H), 7.50 (d, 1H), 7.39 (t, 1H),6.92 (d, 1H), 3.90 (m, 1H), 3.75 (m, 5H), 3.50 (d, 1H), 3.19 (m, 4H),2.91 (d, 1H), 1.40 (s, 3H); LCMS: 470.0 (M+1)⁺.

EXAMPLE 15

5-[4-(3-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound5-[4-(3-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure outlined in Example 1using indane-2-carboxylic acid methyl ester and1-(3-trifluoromethylphenyl)-piperazine. ¹H NMR (400 MHz, MeOH-d₄)

7.65 (s, 1H), 7.60 (d, 1H), 7.45 (d, 1H), 7.38 (t, 1H), 7.15 (d, 1H),7.08 (d, 1H), 3.41 (m, 1H), 3.30 (m, 8H), 3.11 (m, 4H).

EXAMPLE 16

4-[4-(3-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound4-[4-(3-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure outlined in Example 1using indane-2-carboxylic acid methyl ester and1-(3-trifluoromethylphenyl)-piperazine. ¹H NMR (400 MHz, MeOH-d₄)

7.62 (d, 1H), 7.53 (d, 1H), 7.39 (dd, 1H), 7.40 (m, 1H), 7.16 (d, 1H),7.16 (s, 1H), 7.09 (d, 1H), 3.57 (m, 2H), 3.36 (m, 1H), 3.30 (m, 6H),3.23 (m, 4H).

EXAMPLE 175-[4-(4-Trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-sulfonyl]-indan-2-carboxylicacid

Step 1

1-Benzyl-4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine:4-Iodobenzo trifluoride (2.97 g, 10.92 mmol) in THF (50 mL) was addeddropwise over 0.5 h to a solution of n-BuLi (7.5 ml, 1.6 M, 12 mmol) inTHF (50 mL) at −78° C. The reaction mixture was stirred an additional0.5 h upon which N-benzyl-4-piperidone (2.13 g, 11.69 mmol) in THF (10mL) was added over 10 minutes. Stirring was continued for 0.5 h at −78°C., followed by room temperature overnight. The reaction was quenchedwith saturated ammonium chloride and the organic layer was separated.The aqueous layer was extracted with THF and the combined organic layerswere dried (MgSO₄), filtered and concentrated to afford a brown oil. Thecrude product was then dissolved in conc. HCl (30 mL) and 1,4-dioxane (6mL) and stirred at 100° C. overnight. The reaction was poured intosaturated sodium bicarbonate and extracted with ethyl acetate (3×200mL). The combined organic layers were dried (MgSO₄), filtered andconcentrated. The product was purified by silica gel flash columnchromatography (20% ethyl acetate in hexanes) to afford1-benzyl-4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine (981mg, 28%). ¹H NMR (400 MHz, CDCl₃)

7.61 (d, 2H), 7.52 (d, 2H), 7.40 (m, 5H), 6.21 (m, 1H), 3.70 (s, 2H),3.25 (q, 2H), 2.78 (t, 2H), 2.62 (m, 2H); LCMS: 318.4 (M+1)⁺.

Step 2

4-(4-Trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine (HCl):1-Benzyl-4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine wasdissolved in THF (10 mL). The reaction was cooled to −20° C. and1-chloroethylchloroformate (0.5 mL) in THF (2 ml) was added. Thereaction was stirred at −10° C. for 3 h and then concentrated. MeOH (10mL) was added to the crude mixture and refluxed for 2 h. The solvent wasremoved to provide4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine (HCl) which wasused without further purification. ¹H NMR (400 MHz, DMSO-d₆)

9.40 (s, 2H), 7.74 (m, 4H), 6.39 (m, 1H), 3.79 (m, 2H), 3.33 (m, 2H),2.74 (m, 2H).

Step 3

5-[4-(4-Trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-sulfonyl]-indan-2-carboxylicacid: The compound5-[4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-sulfonyl]-indan-2-carboxylicacid was prepared according to the procedure outlined in Example 1 usingindane-2-carboxylic acid methyl ester and4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine. ¹H NMR (400MHz, CDCl₃)

7.66 (m, 2H), 7.57 (d, 2H), 7.39 (m, 3H), 6.06 (m, 1H), 3.79 (m, 2H),3.50-3.26 (m, 7H), 2.63 (m, 2H); LCMS: 451.9 (M+1)⁺.

EXAMPLE 18

4-[4-(4-Trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-sulfonyl]-indan-2-carboxylicacid: The compound4-[4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-sulfonyl]-indan-2-carboxylicacid was prepared according to the procedure outlined in Example 17. ¹HNMR (400 MHz, CDCl₃)

7.69 (d, 1H), 7.57 (d, 2H), 7.44 (d, 1H), 7.41 (d, 2H), 7.34 (t, 1H),6.08 (m, 1H), 3.89 (m, 2H), 3.80-3.31 (m, 7H), 2.61 (m, 2H); LCMS: 451.9(M+1)⁺.

EXAMPLE 19

6-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was prepared according to the procedure outlined in Example 1 usingindane-1-carboxylic acid methyl ester. ¹H NMR (400 MHz, DMSO-d₆)

12.71 (s, 1H), 7.75 (s, 1H), 7.65 (d, 1H), 7.57 (d, 1H), 7.53 (d, 2H),7.06 (d, 2H), 4.17 (t, 1H), 3.40 (m, 4H), 3.03 (m, 6H), 2.36 (m, 2H);LCMS: 454.9 (M+1)⁺.

EXAMPLE 20

6-[4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was prepared according to the procedure outlined in Example 1 usingindane-1-carboxylic acid methyl ester and1-[5-(trifluoromethyl)-pyrid-2-yl]-piperazine. ¹H NMR (400 MHz, CDCl₃)

8.35 (s, 1H), 7.83 (s, 1H), 7.64 (dd, 1H), 7.61 (dd, 1H), 7.39 (d, 1H),6.61 (d, 1H), 4.13 (t, 1H), 3.75 (m, 4H), 3.23-3.10 (m, 1H), 3.11 (m,4H), 3.40-2.94 (m, 1H), 2.48 (m, 2H).

EXAMPLE 21

6-(4-Benzo[1,3]dioxol-5-yl-piperazine-1-sulfonyl)-indan-1-carboxylicacid: The compound6-(4-Benzo[1,3]dioxol-5-yl-piperazine-1-sulfonyl)-indan-1-carboxylicacid was synthesized according to the procedure outlined in Example 1using 1-(3,4-methylendioxybenzyl)piperazine and indane-1-carboxylic acidmethyl ester. ¹H NMR (400 MHz, MeOH-D₄)

7.77 (s, 1H), 7.60 (dd, 1H), 7.47 (d, 1H), 6.78 (s, 1H), 6.73 (m, 2H),5.90 (s, 2H), 4.11 (t, 1H), 3.16-3.09 (m, 1H), 3.04-2.96 (m, 5H),2.58-2.55 (m, 4H), 2.45-2.39 (m, 2H); LCMS.

EXAMPLE 22

6-[4-(4-Trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure outlined in Example 17using indane-1-carboxylic acid methyl ester. ¹H NMR (400 MHz, DMSO-d₆)

12.72 (s, 1H), 7.80 (s, 1H), 7.73-7.69 (m, 3H), 7.61 (d, 2H), 7.55 (d,1H), 6.28 (m, 1H), 4.16 (t, 1H), 3.72 (m, 2H), 3.26 (t, 2H), 3.12-2.92(m, 2H), 2.62 (m, 2H), 2.36 (2H); LCMS: 451.9 (M+1)⁺.

EXAMPLE 23

6-[2-(S)-methyl-4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid

Step 1

3-(S)-Methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine:2-Bromo-5-trifluoromethyl-pyridine (1.06 g, 4.69 mmol),(S)-2-methylpiperazine (1.03 g, 10.28 mmol) and triethylamine (1.5 mL,10.76 mmol) were stirred in toluene (10 mL) at 110° C. for 26 h. Thereaction was cooled to room temperature, diluted with ethyl acetate (150mL) and washed with water and brine. The organic layer was dried(MgSO₄), filtered and concentrated. The crude mixture was purified byautomated silica gel flash column chromatography (gradient eluent 0-20%MeOH/dichloromethane) to afford3-(S)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (926 mg, 81%)as a yellow solid. ¹H NMR (400 MHz, CDCl₃)

8.38 (s, 1H), 7.62 (dd, 1H), 7.63 (d, 1H), 4.29-4.20 (m, 2H), 3.16-3.12(m, 1H), 3.02-2.85 (m, 3H), 2.64-2.52 (m, 2H), 1.18 (d, 3H).

Step 2

6-[2-(S)-Methyl-4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[2-(S)-methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure outlined in Example 1using 3-(S)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine andindane-1-carboxylic acid methyl ester. ¹H NMR (400 MHz, MeOH-d₄)

8.33 (s, 1H), 7.90 (d, 1H, J=5.89 Hz), 7.71-7.67 (m, 1H), 7.62-7.57 (m,1H), 7.35-7.31 (m, 1H), 6.58-6.52 (m, 1H), 4.27-3.96 (m, 4H), 3.80-3.69(m, 1H), 3.37-3.21 (m, 2H), 3.15-2.92 (m, 3H), 2.52-2.40 (m, 2H),1.11-1.08 (m, 3H); LCMS: 470.1 (M+1)⁺.

EXAMPLE 24

6-[2-(R)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[2-(R)-methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure outlined in Example 23using 3-(R)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine andindan-1-carboxylic acid methyl ester. ¹H NMR (400 MHz, MeOH-d₄)

8.33 (s, 1H), 7.90 (d, 1H), 7.71-7.67 (m, 1H), 7.62-7.57 (m, 1H),7.35-7.31 (m, 1H), 6.58-6.52 (m, 1H), 4.27-3.96 (m, 4H), 3.80-3.69 (m,1H), 3.37-3.21 (m, 2H), 3.15-2.92 (m, 3H), 2.52-2.40 (m, 2H), 1.11-1.08(m, 3H); LCMS: 470.0 (M+1)⁺.

EXAMPLE 25

6-[3-(R)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid

Step 1

4-Benzyl-2-(R)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine: Thecompound4-benzyl-2-(R)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine wassynthesized according to the procedure outlined in Example 23 (step 1)using 1-benzyl-3-(R)-methyl-piperazine. ¹H NMR (400 MHz, MeOH-D₄)

8.38 (s, 1H), 7.76 (dd, 1H), 6.90 (d, 1H), 4.80-4.70 (m, 1H), 4.36-4.32(m, 1H), 3.30-3.16 (m, 4H), 3.20-2.92 (m, 1H), 1.29 (d, 3H); LCMS: 336.1(M+1)⁺.

Step 2

2-(R)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine: A solutionof 4-benzyl-2-(R)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine(175 mg, 0.522 mmol) and 10% Pd/C (cat) in ethanol (5 mL) was stirredunder a hydrogen atmosphere (50 psi) for 3d. The reaction mixture wasthen filtered through Celite and purified by silica gel columnchromatography (gradient eluent: 0-20% MeOH in dichloromethane) toprovide the desired product (117 mg, 99%). ¹H NMR (400 MHz, MeOH-D₄)

8.39 (s, 1H), 7.60 (dd, 1H), 7.39-7.28 (m, 5H), 6.58 (d, 1H), 4.49 (brs, 1H), 4.10 (br d, 1H), 3.62 (br d, 1H), 3.47 (br d, 1H), 3.24 (br t,1H), 2.95 (br d, 1H), 2.77 (br d, 1H), 2.35-2.15 (m, 2H), 1.25 (d, 3H);LCMS: 246.1 (M+1)⁺.

Step 3

6-[3-(R)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[3-(R)-methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure outlined in Example 1using 2-(R)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine andindane-1-carboxylic acid methyl ester. ¹H NMR (400 MHz, MeOH-D₄)

8.33 (s, 1H), 7.80 (s, 1H), 7.72-7.62 (m, 2H), 7.46 (dd, 1H), 6.80 (dd,1H), 4.76-4.66 (m, 1H), 4.28 (br d, 1H), 4.14 (br t, 1H), 3.79 (br d,1H), 3.61 (br d, 1H), 3.29-3.20 (m, 1H), 3.16-3.06 (m, 1H), 3.03-2.94(m, 1H), 2.56-2.32 (m, 4H), 1.26 (m, 3H); LCMS: 470.0 (M+1)⁺.

EXAMPLE 266-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid

Step 1

4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acidtert-butyl ester: Tert-butyl-1-piperazine-carboxylate (740 mg, 3.05mmol) and 4-bromo-2-fluoro-1-trifluoromethyl-benzene (530 mg. 2.85 mmol)were dissolved in anhydrous toluene (6 mL, degassed). In a separate,septum-equipped vial were placed tri(dibenzylideneacetone)dipalladium(0) (152 mg, 0.17 mmol), 1,3-bis(2,6-di-1-propylphenyl)imidazoliumchloride (283 mg, 0.67 mmol) and sodium t-butoxide (400 mg, 4.2 mmol).This “catalytic” vial was equipped with a magnetic stirbar and flushedwith dry nitrogen. The reactant solution was next transferred to the“catalytic” vial and the mixture was stirred at 100° C. for 5 hours.After this period the mixture was combined with 20 mL of hexane/EtOAc(2:1) and was passed through a pad of Celite. The resulting filtrate wasconcentrated and purified using silica gel chromatography (0-20%EtOAc/Hexane) to yield 853 mg (86%) of4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acidtert-butyl ester as a yellow residue. ¹H NMR (400 MHz, CDCl₃) δ7.44-7.40 (m, 1H), 6.65-6.58 (m, 2H), 3.59-3.56 (m, 4H), 3.27-3.25 (m,4H), 1.49 (s, 9H).

Step 2

4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine:4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (853 mg, 2.45 mmol) was stirred in a mixture oftrifluoroacetic acid/dichloromethane (5 mL, 25% v/v) for 20 min at roomtemperature. The reaction mixture was combined with 25 mL of CH₂Cl₂ andwas washed with sat'd NaHCO₃ (2×10 mL) and brine. The resulting CH₂Cl₂layer was dried over anhydrous Na₂SO₄ and was concentrated to yieldcrude amine. The product was further purified by silica gelchromatography (gradient eluent 0-10% MeOH in dichloromethane) toprovide 4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazine (473 mg, 78%).The product was used directly in step 3.

Step 3

6-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure outlined in Example 1using 1-(3-fluoro-4-trifluoromethyl-phenyl)-piperazine andindane-1-carboxylic acid methyl ester. ¹H NMR (400 MHz, MeOH-D₄)

7.81 (s, 1H), 7.66-7.63 (m, 1H), 7.49-7.38 (m, 2H), 6.78-6.75 (m, 2H),4.14 (t, 1H), 3.39-3.36 (m, 4H), 3.16-3.07 (m, 5H), 3.03-2.95 (m, 1H),2.46-2.39 (m, 2H); LCMS: 472.9 (M+1)⁺.

EXAMPLE 27

6-[cis-2,6-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[cis-2,6-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure outlined in Example 23using cis-2,6-dimethylpiperazine. ¹H NMR (400 MHz, MeOH-d₄)

8.31 (s, 1H), 7.89 (s, 1H), 7.70 (d, 1H), 7.58 (dd, 1H), 7.31 (d, 1H),6.54 (d, 1H), 4.34-4.26 (m, 1H), 4.20-4.05 (m, 2H), 3.99 (t, 2H),3.13-2.91 (m, 4H), 2.52-2.36 (m, 2H), 1.37 (d, 6H); LCMS: 484.0 (M+1)⁺.

EXAMPLE 286-[cis-2,6-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-1-methyl-indan-1-carboxylicacid

Step 1

1-Methyl-indan-1-carboxylic acid methyl ester: The compound1-methyl-indan-1-carboxylic acid methyl ester was prepared according tothe procedure in Example 13 using indane-1-carboxylic acid methyl ester(67%). ¹H NMR (400 MHz, CDCl₃)

7.32-7.16 (m, 4H), 3.66 (s, 3H), 3.11-3.04 (m, 1H), 2.97-2.90 (m, 1H),2.76-2.70 (d, 1H), 1.99-1.92 (m, 1H), 1.55 (s, 3H).

Step 2

6-[cis-2,6-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-1-methyl-indan-1-carboxylicacid: The compound6-[cis-2,6-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-1-methyl-indan-1-carboxylicacid was synthesized according to the procedure outlined in Example 27using 1-methyl-indan-1-carboxylic acid methyl ester and 2,6-dimethylpiperazine. ¹H NMR (400 MHz, MeOH-d₄)

8.26 (s, 1H), 7.96 (dd, 1H), 7.65 (dd, 1H), 7.32 (d, 1H), 4.30-4.22 (m,1H), 4.18-4.11 (m, 1H), 4.04-3.98 (m, 1H), 3.35 (s, 3H), 3.08-2.92 (m,4H), 2.76-2.70 (m, 1H), 2.04-1.97 (m, 1H), 1.55 (s, 3H), 1.36-1.33 (m,6H); LCMS: 498.1 (M+1)⁺.

EXAMPLE 29{6-Methoxy-5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-yl}-aceticacid

Step 1

(6-Methoxy-indan-1-ylidene)-acetic acid ethyl ester:6-Methoxy-indan-1-one (5.02 g, 30.95 mmol) and triethyl phosphonoacetate(15.5 mL, 78.13 mmol) was dissolved in THF (20 mL) and added slowly to amixture of EtOH (850 μL) and NaH (60% dispersion in oil, 2.5 g). Theresulting slurry was stirred at 70° C. overnight. The crude mixture wasdiluted with diethyl ether and washed with water and brine, dried(Na₂SO₄), filtered and concentrated. The product was purified by silicagel flash column chromatography (5:1 hexanes in ethyl acetate) to afford(6-Methoxy-indan-1-ylidene)-acetic acid ethyl ester (3.18 g, 47%) as amixture (˜1:1) of E/Z isomers. ¹H NMR (400 MHz, CDCl₃) mixture (˜1:1) ofE/Z isomers

7.37 (d, 1H) 7.27 (d, 1H), 7.09 (d, 1H), 6.99 (dd, 1H), 6.97 (d, 1H),6.81 (dd, 1H), 6.50 (m, 1H), 6.31-6.30 (m, 1H), 4.27 (quart, 2H), 4.22(quart, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.60 (m, 2H), 3.36-3.33 (m,4H), 3.05-3.02 (m, 2H), 1.37 (t, 3H), 1.31 (t, 3H).

Step 2

(6-Methoxy-indan-1-yl)-acetic acid ethyl ester:(6-methoxy-indan-1-ylidene)-acetic acid ethyl ester (3.18 g, 14.5 mmol)was dissolved in MeOH (30 ml). A catalytic amount of 10% Pd/C was addedand the reaction was stirred under an atmosphere of hydrogen (balloon)for 2 h. The reaction mixture was filtered through Celite to providepure (6-methoxy-indan-1-yl)-acetic acid ethyl ester (2.98 g, 94%) as aclear oil. LCMS: 235.0 (M+1)⁺.

Step 3

{6-Methoxy-5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-yl}-aceticacid: The compound{6-methoxy-5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-yl}-aceticacid was synthesized according to the procedure outlined in example 1using (6-methoxy-indan-1-yl)-acetic acid ethyl ester. ¹H NMR (400 MHz,MeOH-d₄)

7.67 (s, 1H) 7.46 (d, 2H), 7.10 (s, 1H), 7.01 (d, 2H), 3.89 (s, 3H),3.57 (quint., 1H), 3.30 (m, 8H), 2.96-2.78 (m, 3H), 2.49-2.37 (m, 2H),1.85-1.76 (m, 1H); LCMS: 498.9 (M+1)⁺.

EXAMPLE 30

{5-[4-(3,4-Dichloro-phenyl)-piperazine-1-sulfonyl]-6-methoxy-indan-1-yl}-aceticacid:{5-[4-(3,4-dichloro-phenyl)-piperazine-1-sulfonyl]-6-methoxy-indan-1-yl}-aceticacid was synthesized according to the procedure outlined in Example 29using 3,4-dichlorophenyl piperazine. ¹H NMR (400 MHz, MeOH-d₄)

7.64 (s, 1H) 7.28 (d, 1H), 7.14-7.12 (s, 1H), 7.04 (d, 1H), 6.85 (dd,1H), 3.90 (s, 3H), 3.60 (quint., 1H), 3.30-3.27 (m, 4H), 3.19-3.17 (m,4H), 2.95-2.76 (m, 2H), 2.60 (dd, 1H), 2.43-2.33 (m, 2H), 1.85-1.76 (m,1H); LCMS: 498.8 (M+1)⁺.

EXAMPLE 31

{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid

Step 1

1-{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-ethanone:The compound1-{5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-ethanonewas synthesized according to the procedure outlined in Example 1 using1-acetyl indoline (89%). ¹H NMR (400 MHz, CDCl₃) δ 8.43 (d 1H), 7.62 (d,1H), 7.57 (s, 1H), 7.47 (d, 2H), 6.88 (d, 2H), 4.16 (t, 2H), 3.35 (m,4H), 3.28 (t, 2H), 3.15 (m, 4H), 2.27 (s, 3H); LCMS: 454.0 (M+1)⁺.

Step 2

5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-1H-indole:1-{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-ethanonewas refluxed in 1,4-dioxane (5 mL) and concentrate HCl (2.5 mL) for 2 h.The reaction was then diluted with dichloromethane and washed with 1NHCl, saturated sodium bicarbonate, dried (Na₂SO₄), filtered andconcentrated to provide5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-1H-indole(1.03 g, 75%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃)

7.48-7.20 (m, 4H) 6.88 (d, 2H), 6.60 (d, 1H), 3.70 (t, 2H), 3.36-3.33(m, 4H), 3.15-3.12 (m, 4H), 3.10 (t, 2H).

Step 3

5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-1H-indole:5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-1H-indole(180 mg, 0.44 mmol) was dissolved in dichloromethane (10 mL). DDQ (100mg, 0.44 mmol) was added and stirred at room temperature for 4 h. Thereaction was concentrated and purified by silica gel flash columnchromatography (45% ethyl acetate in hexanes) to provide5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-1H-indole (70%)as a white solid. ¹H NMR (400 MHz, DMSO-D₆)

11.72 (s, 1H), 8.07 (s, 1H) 7.65 (d, 1H), 7.62-7.61 (m, 1H), 7.52-7.48(m, 3H), 7.04 (d, 2H), 6.71 (m, 1H), 3.40-3.36 (m, 4H), 3.02-2.99 (m,4H).

Step 4

{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid methyl ester:5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-1H-indole (60 mg,0.15 mmol), methyl bromo acetate (16 μL, 0.18 mmol) and cesium carbonate(95 mg, 0.29 mmol) were stirred in acetonitrile (10 ml) overnight at 70°C. The reaction mixture was diluted with ethyl acetate, washed withwater, brine, dried (Na₂SO₄) and concentrated to provide{5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid methyl ester (99%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.11(d, 1H) 7.60 (dd, 1H), 7.43 (d, 2H), 7.36 (d, 1H), 7.24 (d, 1H), 6.83(d, 2H), 6.90 (d, 1H), 4.91 (s, 2H), 3.76 (s, 3H), 3.32-3.30 (m, 4H),3.15-3.13 (m, 4H).

Step 5

{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid: The compound{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid methyl ester was hydrolyzed according to the procedure outlined inExample 1 (99%). ¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, 1H) 7.70 (dd, 1H),7.60 (d, 1H), 7.53 (m, 3H), 7.04 (d, 2H), 6.74 (d, 1H), 5.16 (s, 2H),3.39 (m, 4H), 3.01 (m, 4H).

EXAMPLE 32

{5-Bromo-6-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid:{5-Bromo-6-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid was synthesized according to the procedure outlined in Example 31using 1-(5-Bromo-2,3-dihydro-indol-1-yl)-ethanone as the startingmaterial. ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H) 7.95 (s, 1H), 7.46 (d,2H), 7.28 (d, 1H), 6.88 (d, 2H), 6.56 (d, 1H), 4.94 (s, 2H), 3.44-3.42(m, 4H), 3.28-3.26 (m, 4H).

EXAMPLE 33

{5-Bromo-6-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid:{5-Bromo-6-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid was synthesized according to the procedure outlined in Example 31using 1-(5-Bromo-2,3-dihydro-indol-1-yl)-ethanone and1-[5-(trifluoromethyl)-pyrid-2-yl]piperazine. ¹H NMR (400 MHz, CDCl₃) δ8.24 (s, 1H) 8.07 (s, 1H), 7.87 (s, 1H), 7.63 (dd, 1H), 7.23 (d, 1H),6.61 (d, 1H), 6.46 (d, 1H), 5.30 (s, 2H), 3.66-3.63 (m, 4H), 3.34-3.32(m, 4H).

EXAMPLE 34

{6-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid

Step 1

{5-Bromo-6-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid methyl ester: The compound{5-bromo-6-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid methyl ester was synthesized according to the procedure outlined inExample 31 using 1-(5-bromo-2,3-dihydro-indol-1-yl)-ethanone as thestarting material. ¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H) 7.98 (s, 1H),7.47 (d, 2H), 7.31 (d, 1H), 6.90 (d, 2H), 6.58 (d, 1H), 4.11 (dd, 2H),3.79 (s, 3H), 3.45 (m, 4H), 3.32 (m, 4H).

Step 2

{6-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid methyl ester:{5-Bromo-6-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid methyl ester (135 mg, 0.24 mmol), triethylamine (40 μL, 0.29 mmol)and 10% Pd/carbon (cat) were stirred under an atmosphere of hydrogenuntil all the starting material was gone. The reaction was then filteredthrough celite, concentrated and purified by flash column chromatography(60% hexanes in ethyl acetate) to afford{6-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid methyl ester (96 mg, 83%) as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ7.76 (d, 1H) 7.75 (d, 1H), 7.51 (dd, 1H), 7.44 (dd, 2H), 7.31 (d, 1H),6.84 (d, 2H), 6.67 (d, 1H), 4.11 (dd, 2H), 3.78 (s, 3H), 3.33 (m, 4H),3.16 (m, 4H).

Step 3

{6-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid:{6-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid methyl ester was hydrolyzed according to the procedure in Example 1(87%). ¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, 1H) 7.82 (d, 1H), 7.67 (d,1H), 7.50 (d, 2H), 7.42 (dd, 1H), 7.03 (d, 2H), 6.60 (d, 1H), 5.20 (s,2H), 3.37 (m, 4H), 3.02 (m, 4H).

EXAMPLE 35

{6-[4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid: The compound{6-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid was synthesized according to the procedure outlined in Example 34using 1-[5-(trifluoromethyl)-pyrid-2-yl]piperazine. ¹H NMR (400 MHz,CDCl₃) δ 8.31 (s, 1H), 7.73 (d, 1H) 7.72 (s, 1H), 7.58 (dd, 1H), 7.48(dd, 1H), 7.30 (d, 1H), 6.64 (d, 1H), 6.56 (d, 1H), 4.93 (s, 2H), 3.74(m, 4H), 3.10 (m, 4H).); LCMS: 468.9 (M+1)⁺.

EXAMPLE 36

{6-Methoxy-7-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid

Step 1

4-(3-Methoxy-phenylsulfanyl)-3-oxo-butyric acid ethyl ester: A solutionof ethyl-4-chloroacetoacetate (8.75 g, 71.2 mmol) in 20 mL ofacetonitrile was added slowly to a mixture of 3-methoxybenzenethiol(9.69 g, 71.2 mmol) and cesium carbonate (46.4 g, 14.2 mmol) inacetonitrile (200 mL) over 5 minutes. The mixture was stirred at roomtemperature for 2 hours and filtered through a bed of Celite.Evaporation of the filtrate gave an oil which solidified on standing.The residue was dissolved in EtOAc, and the solution was sequentiallywashed with H₂O, brine, and dried over Na₂SO₄. Evaporation of solventafforded 14.0 g of desired ester. ¹H NMR (400 MHz, CDCl₃) δ 7.20 (t,1H), 6.90 (d, 1H), 6.87 (s, 1H), 6.79 (d, 1H), 4.20 (q, 2H), 3.82 (s,2H), 3.79 (s, 3H), 3.63 (s, 2H), 1.26 (t, 3H).

Step 2

(6-Methoxy-benzo[b]thiophen-3-yl)-acetic acid ethyl ester: Compound fromstep 1 (7.0 g, 26.0 mmol) was slowly added to methanesulfonic acid (100mL) at room temperature. The resulting solution was stirred for 20minutes and added dropwise into ice (250 g). The aqueous mixture wasextracted two times with EtOAc. The organic layer was washed with brine,saturated NaHCO₃, and dried over Na₂SO₄. After removal of solvent, theresidue was purified by chromatography on silica gel (3:7 EtOAc/hexane)to give 4.33 g of desired compound.

Step 3

(7-Chlorosulfonyl-6-methoxy-benzo[b]thiophen-3-yl)-acetic acid ethylester: To a solution of compound from step 2 (1.0 g, 4.0 mmol) in CH₂Cl₂(10 mL) was added chlorosulfonic acid (0.56 mL, 8.0 mmol). The resultingmixture was stirred for 4 hours at room temperature. The solvent wasevaporated in vacuo and the residue was dissolved in EtOAc. The solutionwas washed with Na₂CO₃, brine and dried over Na₂SO₄. Evaporation ofsolvent afforded 50 mg of desired compound. ¹H NMR (400 MHz, CDCl₃) δ8.08 (d, 1H), 7.38 (s, 1H), 6.90 (d, 1H), 4.21 (q, 2H), 4.02 (s, 2H),4.01 (s, 3H), 1.24 (t, 3H).

Step 4

{6-Methoxy-7-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid ethyl ester: To a solution of compound from step 3 (50 mg, 0.14mmol) in THF (2 mL) was added1-[5-(trifluoromethyl)-2-pyridinyl]piperazine (32 mg, 0.14 mmol),followed by triethylamine (39 μL, 0.28 mmol). The reaction solution wasstirred for 4 hours at room temperature. The solvent was evaporated andthe residues were purified by silica gel chromatography to afford 22 mgof desired compound.

Step 5

{6-Methoxy-7-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid: Compound from step 4 (22 mg, 0.041 mmol) was dissolved in 2 mL ofTHF/MeOH (3:1), followed by addition of 1N LiOH (5.0 eqv). The resultingmixture were stirred at 40° C. for 3 hours. The organic solvent wasevaporated under N₂ and residues were diluted with water (2 mL). Theaqueous layers were partitioned with ether (2 mL). After removal oforganic layers, the aqueous layers were neutralized by 1N HCl (5.0 eqv)and then extracted with ethyl acetate (5 mL). The organic layers werewashed with H₂O, brine, and dried over Na₂SO₄. The solution wasconcentrated in vacuo to afford{6-Methoxy-7-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid. ¹H NMR (400 MHz, CDCl₃) δ 8.32 (s, 1H), 8.38 (s, 1H), 7.78 (d,1H), 7.61 (d, 1H), 7.22 (s, 1H), 6.60 (m, 1H), 4.01 (s, 2H), 3.98 (s,3H), 3.77 (m, 4H), 3.22 (m, 4H).

EXAMPLE 37

{5-[4-(5-Trifluoromethyl-pyridin-2-yl)piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid: The compound of{5-[4-(5-Trifluoromethyl-pyridin-2-yl)piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid was prepared according to the method used to prepare Example 36using benzo[b]thiophen-3-yl-acetic acid methyl ester. ¹H NMR (400 MHz,CDCl₃) δ 8.33 (s, 1H), 8.32 (s, 1H), 7.87 (d, 1H), 7.78 (d, 1H), 7.65(s, 1H), 7.62 (d, 1H), 6.59 (d, 1H), 3.93 (s, 2H), 3.78 (m, 4H), 3.14(m, 4H).

EXAMPLE 38

6-[2,2-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid

The compound6-[2,2-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was prepared according to the method used to prepare Example 26using 2,2-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)piperazine. ¹H NMR(400 MHz, CDCl₃) δ 8.36 (s, 1H), 7.91 (s, 1H), 7.71 (d, 1H), 7.61 (d,1H), 7.36-7.31 (m, 1H), 6.52 (d, 1H), 4.15-4.11 (m, 1H), 3.73-3.53 (m,6H), 3.18-3.12 (m, 1H), 3.10-2.95 (m, 1H), 2.54-2.42 (m, 2H), 1.39 (s,6H). ESMS (M+H): 484.1.

EXAMPLE 39

(R)-4-(3-Carboxy-indane-5-sulfonyl)-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylicacid methyl ester

Step 1

Indan-1-carboxylic acid 4-nitro-benzyl ester: To a solution of3H-Indene-1-carboxylic acid (2.0 g, 13.3 mmol) in ethanol (35 mL) wasadded 10% Pd/C (200 mg). The reaction mixture was stirred under an H₂atmosphere for 1 h. The mixture was filtered through Celite andconcentrated in vacuo. The residue was combined with p-nitrobenzylbromide (5.8 g, 26.8 mmoles) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.4mL, 16.0 mmol) in 65 mL of benzene, and was stirred at 50° C. for 20hours. After this period the heterogeneous mixture was gravity filteredand the filtrate was evaporated in vacuo. The residue was combined withCH₂Cl₂ and was washed with 1N HCl (2×25 mL) and sat'd NaHCO₃ (2×25 mL),and the resulting CH₂Cl₂ solution was dried over anhydrous Na₂SO₄. Thecrude solid was purified using flash silica chromatography (0-10%EtOAc/Hexane) to yield 3.61 g (95%) of the intermediate.

Step 2

6-Chlorosulfonyl-indan-1-carboxylic acid 4-nitro-benzyl ester: To asolution of indan-1-carboxylic acid 4-nitro-benzyl ester (2.3 g, 8.1mmol) in anhydrous CHCl₃ (13 mL) at −20° C. was added chlorosulfonicacid (2.8 g, 24.0 mmol) over a period of 10 minutes. The mixture waswarmed to ambient temperature and stirred for 16 h. The reaction mixturewas combined with ice-water and the resulting layer was extracted withCH₂Cl₂. The CH₂Cl₂ layer was washed with brine and was dried overanhydrous Na₂SO₄. The crude product was purified using flash silicachromatography (0-30% EtOAc/Hex) to yield 0.84 g (27%) of6-chlorosulfonyl-indan-1-carboxylic acid 4-nitro-benzyl ester.

Step 3

4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester: 3-Methyl-piperazine-1,3-dicarboxylicacid 1-tert-butyl ester (120 mg, 0.49 mmol) and2-Bromo-5-trifluoromethyl-pyridine (133 mg, 0.59 mmol) were dissolved in2.0 mL of anhydrous toluene (degassed). In a separate, septum-equippedvial were placed tri(dibenzylideneacetone)dipalladium (0) (22 mg, 0.024mmol), 1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride (42 mg, 0.1mmol) and sodium t-butoxide (57 mg, 0.59 mmol). This “catalytic” vialwas equipped with a magnetic stir bar and flushed with dry nitrogen. Thereactant solution was next transferred to the “catalytic” vial and themixture was stirred at 100° C. for 5 h. After this period the mixturewas combined with 20 mL of hexane/EtOAc (2:1) and was passed through apad of Celite. The resulting filtrate was evaporated in vacuo andpurified using flash silica chromatography (0-20% EtOAc/Hexane) to yield110 mg (58%) of4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester.

Step 4

4-[3-(4-Nitro-benzyloxycarbonyl)-indane-5-sulfonyl]-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylicacid methyl ester:4-(5-Trifluoromethyl-pyridin-2-yl)-piperazine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester (110 mg, 0.28 mmol) was combined with2.0 mL of 25% TFA/CH₂Cl₂ and was stirred at room temperature for 30 min.After this period the reaction mixture was diluted with CH₂Cl₂ (25 mL)and was washed with sat'd NaHCO₃ (2×10 mL) and brine. The resultingCH₂Cl₂ layer was dried over anhydrous Na₂SO₄ and was evaporated in vacuoto yield crude amine. The crude amine was purified using flash silicachromatography (0-10% MeOH/CH₂Cl₂) to yield 77 mg (94%) of(R)-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylic acidmethyl ester as a yellow residue. This material was combined with6-Chlorosulfonyl-indan-1-carboxylic acid 4-nitro-benzyl ester from Step2 (102 mg, 0.27 mmoles) and triethylamine (46 μL, 0.33 mmol) in 2.0 mLof anhydrous THF, and was stirred at 60° C. for 5 hours. After thisperiod the reaction mixture was evaporated in vacuo and the resultingresidue was combined with 30 mL of benzene. The resulting heterogeneousmixture was filtered with benzene washings. The filtrate was thenevaporated in vacuo and purified using flash silica chromatography(0-30% EtOAc/Hexane) to yield4-[3-(4-Nitro-benzyloxycarbonyl)-indane-5-sulfonyl]-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylicacid methyl ester.

Step 5

(R)-4-(3-Carboxy-indane-5-sulfonyl)-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylicacid methyl ester:4-[3-(4-Nitro-benzyloxycarbonyl)-indane-5-sulfonyl]-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylicacid methyl ester (87 mg, 0.14 mmol) obtained from step 4 was combinedwith 10% Pd/C (75 mg), cyclohexadiene (260 μL, 2.8 mmol) and 2.0 mL ofethanol within an 8 mL Teflon-capped vial. This mixture was stirred at70° C. for 6 h and then passed through a Celite plug (with MeOHwashings). The resulting filtrate was evaporated in vacuo, and the cruderesidue was purified using flash silica chromatography (0-10%MeOH/CH₂Cl₂) to yield(R)-4-(3-Carboxy-indane-5-sulfonyl)-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylicacid methyl ester. ¹H NMR (400 MHz, CD₃OD) δ 8.37 (m, 1H), 7.85 (s, 1H),7.80 (d, 1H), 7.69 (d, 1H), 7.52 (d, 1H), 6.94 (d, 1H), 5.55 (m, 1H),4.33-4.29 (m, 1H), 4.20-4.11 (m, 2H), 3.84-3.81 (m, 1H), 3.74 (s, 3H),3.47-3.41 (m, 1H), 3.20-3.14 (m, 1H), 3.07-2.99 (m, 1H), 2.65-2.61 (m,1H), 2.51-2.42 (m, 3H). ESMS (M+H): 514.0

EXAMPLE 40

(S)-4-(3-Carboxy-indane-5-sulfonyl)-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylicacid methyl ester: The compound of(S)-4-(3-carboxy-indane-5-sulfonyl)-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylicacid methyl ester was prepared according to the method used to prepareexample 39. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (m, 1H), 7.85 (s, 1H),7.69-7.62 (m, 2H), 7.41 (d, 1H), 6.68-6.01 (m, 1H), 5.53 (m, 1H), 4.35(d, 1H), 4.16-4.13 (m, 1H), 3.90-3.82 (m, 2H), 3.74 (s, 3H), 3.60-3.51(m, 1H), 3.19-3.11 (m, 1H), 3.03-2.95 (m, 1H), 2.64-2.60 (m, 1H),2.52-2.46 (m, 3H). ESMS (M+H): 514.0

EXAMPLE 41

{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid: The compound{5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid was prepared followed the procedure for Example 37 using1-(4-trifluoromethyl-phenyl)-piperazine. ¹H NMR (400 MHz, CDCl₃), δ 8.34(s, 1H), 7.90 (d, 1H), 7.76 (d, 1H), 7.65 (s, 1H), 7.45 (d, 2H), 6.85(d, 2H), 3.94 (s, 2H), 3.34 (m, 4H), 3.20 (m, 4H).

EXAMPLE 42

{5-[2-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid: The compound{5-[2-methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid was prepared followed the procedure for Example 37 using3-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine. ¹H NMR (400 MHz,CDCl₃), δ 8.38 (s, 1H), 8.32 (s, 1H), 7.82 (m, 2H), 7.63 (s, 1H), 7.55(d, 1H), 6.48 (d, 1H), 4.29 (m, 1H), 4.18 (d, 1H), 4.02 (d, 1H), 3.92(s, 2H), 3.79 (d, 1H), 3.28 (m, 2H), 3.02 (t, 1H), 1.10 (d, 3H).

EXAMPLE 43

{5-[cis-2,6-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid: The compound{5-[2,6-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid was prepared followed the procedure for Example 37 usingcis-2,6-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine ¹H NMR(400 MHz, CDCl₃), δ 8.37 (s, 1H), 8.29 (s, 1H), 7.81 (m, 2H), 7.62 (s,1H), 7.52 (d, 1H), 6.44 (d, 1H), 4.27 (m, 2H), 3.96 (t, 2H), 3.91 (s,2H), 3.03 (dd, 2H), 1.39 (d, 6H).

EXAMPLE 44

{5-[2,5-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid: The compound{5-[2,5-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid was prepared followed the procedure for Example 37 using2,5-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine. ¹H NMR (400MHz, CDCl₃), δ 8.39 (s, 1H), 8.37 (s, 1H), 7.87 (d, 1H), 7.79 (d, 1H),7.64 (s, 1H), 7.61 (d, 1H), 6.57 (d, 1H), 4.63 (m, 1H), 4.31 (m, 1H),4.05 (d, 1H), 3.94 (s, 2H), 3.61 (d, 1H), 3.37 (m, 2H), 1.21 (d, 3H),0.96 (d, 3H).

EXAMPLE 45

6-[4-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26.¹H NMR (400 MHz, CD₃OD) δ 7.83 (s, 1H), 7.65 (dd, 1H), 7.51 (d, 1H),7.38 (d, 1H), 7.32 (dd, 1H), 7.14-7.10 (m, 1H), 4.15 (t, 1H), 3.30-3.20(m, 4H), 3.20-3.15 (m, 1H), 3.14-3.10 (m, 4H), 3.09-2.96 (m, 1H), 2.49(q, 2H); LCMS 472.5 (M+1)⁺.

EXAMPLE 46

6-[4-(3,4-Dichloro-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[4-(3,4-dichloro-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26.¹H NMR (400 MHz, CD₃OD) δ 7.84 (s, 1H), 7.70 (d, 1H), 7.54 (d, 1H),7.34-7.29 (m, 1H), 7.10-7.06 (m, 1H), 6.90-6.84 (m, 1H), 4.38 (t, 1H),3.30-3.22 (m, 4H), 3.21-3.25 (m, 1H), 3.24-3.10 (m, 4H), 3.20-2.99 (m,1H), 2.50 (q, 2H); LCMS 455.5 (M+1)⁺.

EXAMPLE 47

{5-[4-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid

Step 1

1-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine: The compound1-(2-fluoro-4-trifluoromethyl-phenyl)-piperazine is synthesizedaccording to the procedure outlined in Example 26 steps 1 and 2 usingt-butyl-1-piperazine-carboxylate and1-bromo-2-fluoro-4-trifluoromethyl-benzene.

Step 2

{5-[4-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid: The compound{5-[4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid was synthesized according to the procedure in Example 37 using1-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine obtained in step 1above. ¹H NMR (400 MHz, CD₃OD) δ 8.44 (s, 1H), 8.04 (d, 1H), 7.82 (s,1H), 7.78 (dd, 1H), 7.46-7.38 (m, 1H), 6.80-8.72 (m, 2H), 3.98 (s, 2H),3.42-3.32 (m, 4H), 3.19-3.10 (m, 4H); LCMS 502.5 (M+1)⁺.

EXAMPLE 48

{5-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid: The compound{5-[4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid was synthesized according to the procedure described in Example 47.¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 8.10 (d, 1H), 7.81 (s, 1H), 7.78(dd, 1H), 7.46-7.39 (m, 1H), 6.80-8.72 (m, 2H), 4.00 (s, 2H), 3.40-3.31(m, 4H), 3.18-3.10 (m, 4H); LCMS 502.5 (M+1)⁺.

EXAMPLE 49

6-[4-(3,4-Dichloro-phenyl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[4-(3,4-dichloro-phenyl)-2,6-cis-dimethyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26Steps 1 and 3 using 2,6-cis-dimethyl-piperazine and4-bromo-1,2-dichloro-benzene. ¹H NMR (400 MHz, CD₃OD) δ 7.83 (d, 1H),7.67-7.62 (m, 1H), 7.38 (dd, 1H), 7.19 (d, 1H), 6.82 (d, 1H), 6.65 (dd,1H), 4.30-4.21 (m, 1H), 4.20-4.10 (m, 2H), 3.25-3.20 (m, 2H), 3.19-3.10(m, 1H), 3.08-2.89 (m, 1H), 2.65-2.56 (m, 2H), 2.45-2.39 (m, 2H), 1.48(d, 3H), 1.45 (d, 3H); LCMS 483.4 (M+1)⁺.

EXAMPLE 50

6-[4-(3-Chloro-4-trifluoromethyl-phenyl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[4-(3-Chloro-4-trifluoromethyl-phenyl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26Steps 1 and 3 using 2,6-cis-dimethyl-piperazine and4-bromo-2-chloro-1-trifluoromethyl-benzene. ¹H NMR (400 MHz, CD₃OD) δ7.87 (s, 1H), 7.69 (d, 1H), 7.45 (d, 1H), 7.38 (d, 1H), 6.85 (s, 1H),6.72 (d, 1H), 4.28-4.21 (m, 1H), 4.18-4.10 (m, 1H), 4.08 (t, 1H),3.48-3.40 (m, 1H), 3.38-3.18 (m, 3H), 3.10-2.89 (m, 2H), 2.48-2.38 (m,2H), 1.42 (m, 3H) 1.40 (d, 3H); LCMS 516.9 (M+1)⁺.

EXAMPLE 51

6-[cis-2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[2,6-cis-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26Steps 1 and 3 using cis-2,6-dimethyl-piperazine and1-bromo-4-trifluoromethoxy-benzene. ¹H NMR (400 MHz, CD₃OD) δ 7.84 (s,1H), 7.70 (d, 1H), 7.40 (d, 1H), 7.10 (d, 2H), 6.89 (d, 2H), 4.30-4.20(m, 1H), 4.19-4.09 (m, 2H), 3.30-3.20 (m, 2H), 3.19-3.10 (m, 1H),3.08-2.98 (m, 1H), 2.65-2.56 (m, 2H), 2.45-2.39 (m, 2H), 1.50 (d, 3H),1.45 (d, 3H); LCMS 498.5 (M+1)⁺.

EXAMPLE 52

6-[4-(3,4-Dichloro-phenyl)-3-(S)-methyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[4-(3,4-dichloro-phenyl)-3-(S)-methyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26using 3-(S)-methyl-piperazine-1-carboxylic acid tert-butyl ester and4-bromo-1,2-dichloro-benzene. ¹H NMR (400 MHz, CD₃OD) δ 7.88 (s, 1H),7.65 (d, 1H), 7.45 (d, 1H), 7.32 (d, 1H), 7.15-6.94 (m, 1H), 6.78-6.72(m, 1H), 4.20-4.10 (m, 1H), 4.10-4.00 (m, 2H), 3.70-3.60 (m, 1H),3.45-3.40 (m, 1H), 3.30-3.21 (m, 2H), 3.20-3.11 (m, 1H), 3.10-2.90 (m,1H), 2.75-2.60 (m, 1H) 2.48-2.40 (m, 2H), 1.20 (d, 3H); LCMS 469.4(M+1)⁺.

EXAMPLE 53

6-[3-(S)-Methyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[3-(S)-methyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26using 3-(S)-methyl-piperazine-1-carboxylic acid tert-butyl ester and1-bromo-4-trifluoromethoxy-benzene. ¹H NMR (400 MHz, CD₃OD) δ 7.81 (s,1H), 7.66 (d, 1H), 7.50 (d, 1H), 7.62 (d, 2H), 6.98-6.93 (m, 2H), 4.18(t, 1H), 4.00-3.90 (m, 1H), 3.60-3.55 (m, 1H), 3.35-3.25 (m, 3H),3.20-3.10 (m, 1H), 3.10-3.00 (m, 1H), 2.85-2.75 (m, 1H), 2.70-2.60 (m,1H) 2.40 (q, 2H), 1.10 (d, 3H); LCMS 484.5 (M+1)⁺.

EXAMPLE 54

6-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-3-(S)-Methyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-3-(S)-Methyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26using 3-(S)-methyl-piperazine-1-carboxylic acid tert-butyl ester. ¹H NMR(400 MHz, CD₃OD) δ 7.80 (s, 1H), 7.70 (d, 1H), 7.50 (d, 1H), 7.41-7.31(m, 2H), 7.20-7.10 (m, 1H), 4.20-4.10 (m, 1H), 3.90-3.78 (m, 1H),3.50-3.40 (m, 1H), 3.39-3.20 (m, 3H), 3.19-3.10 (m, 1H), 3.09-2.98 (m,2H), 2.80-2.70 (m, 1H), 2.42-2.25 (m, 2H), 1.10 (d, 3H); LCMS 486.5(M+1)⁺.

EXAMPLE 55

6-[3-(S)-Methyl-4-(5-trifluoromethyl-phenyl-pyridin-2-yl))-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[3-(S)-methyl-4-(5-trifluoromethyl-phenyl-pyridin-2-yl))-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26using 3-(S)-methyl-piperazine-1-carboxylic acid tert-butyl ester and2-bromo-5-trifluoromethyl-pyridine. ¹H NMR (400 MHz, CD₃OD) δ 8.38 (s,1H), 7.83 (s 1H), 7.78-7.72 (m, 1H), 7.65 (d, 1H), 7.50-7.40 (m, 1H),6.85-6.80 (m, 1H), 4.80-4.70 (m, 1H), 4.30 (d, 1H), 4.20-4.10 (m, 2H),3.81 (d, 1H), 3.60 (d, 1H), 2.35-2.24 (m, 1H), 3.20-3.11 (m, 1H),3.10-2.98 (m, 1H), 2.60-2.45 (m, 1H) 2.42-2.25 (m, 2H), 1.40-1.20 (m,3H); LCMS 469.5 (M+1)⁺.

EXAMPLE 56

6-[4-(3-Chloro-4-trifluoromethyl-phenyl)-2-ethyl-piperazine-1-sulfonyl]-indan-1carboxylicacid: The compound6-[4-(3-chloro-4-trifluoromethyl-phenyl)-2-ethyl-piperazine-1-sulfonyl]-indan-1carboxylicacid was synthesized according to the procedure described in Example 26Steps 1 and 3 using 2-ethyl-piperazine and4-bromo-2-chloro-1-trifluoromethyl-benzene. ¹H NMR (400 MHz, CD₃OD) δ7.90 (d, 1H), 7.72 (t, 1H), 7.45 (dd, 1H), 7.38 (dd, 1H), 6.87 (dd, 1H),6.70 (dd, 1H), 4.12-4.02 (m, 1H), 4.01-3.93 (m, 1H), 3.98-3.76 (m, 1H),3.58-3.42 (m, 2H), 3.41-3.29 (m, 1H), 3.11-3.02 (m, 1H), 3.00-2.82 (m,2H), 2.82-2.62 (m, 1H), 2.46-2.36 (m, 2H), 1.76-1.56 (m, 2H), 1.00-0.92(m 3H); LCMS 516.9 (M+1)⁺.

EXAMPLE 57

6-[2-Ethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[2-ethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26Steps 1 and 3 using 2-ethyl-piperazine and1-bromo-4-trifluoromethoxy-benzene. ¹H NMR (400 MHz, CD₃OD) δ 7.90 (s,1H), 7.79-7.73 (m, 1H), 7.47-7.38 (m, 1H), 7.08 (d, 2H), 6.88-6.81 (m,2H), 4.12 (q, 1H), 3.99-3.90 (m, 1H), 3.88-3.76 (m, 1H), 3.44-3.24 (m,3H), 3.16-3.08 (m, 1H), 3.02-2.92 (m, 1H), 2.69-2.50 (m, 2H), 2.48-2.36(m, 2H), 1.82-1.66 (m, 2H), 0.95 (t, 3H); LCMS 498.5 (M+1)⁺.

EXAMPLE 58

6-[4-(3,4-Dichloro-phenyl)-2-ethyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[4-(3,4-Dichloro-phenyl)-2-ethyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26Steps 1 and 3 using 2-ethyl-piperazine and 4-bromo-1,2-dichloro-benzene.¹H NMR (400 MHz, CD₃OD) δ 7.84 (s, 1H), 7.68-7.64 (m, 1H), 7.39-7.32 (m,1H), 7.19 (dd, 1H), 6.82 (dd, 1H), 6.68-6.62 (m, 1H), 4.10 (q, 1H),3.98-3.83 (m, 1H), 3.81-3.71 (m, 1H), 3.30-3.20 (m, 3H), 3.12-3.02 (m,1H), 3.00-2.90 (m, 1H), 2.70-2.60 (m, 2H), 2.40-2.30 (m, 2H), 1.55-1.51(m, 2H), 0.98 (t, 3H); LCMS 483.4 (M+1)⁺.

EXAMPLE 59

6-[2-Ethyl-4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[2-Ethyl-4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26Steps 1 and 3 using 2-ethyl-piperazine. ¹H NMR (400 MHz, CD₃OD) δ 8.10(s, 1H), 7.98-7.83 (m, 1H), 7.79 (d, 1H), 7.51-7.48 (m, 1H), 6.71-6.60(m, 2H), 4.09-3.91 (m, 2H), 3.86-3.76 (m, 1H), 3.60-3.44 (m, 2H),3.30-3.20 (m, 1H), 3.14-3.01 (m, 1H), 2.98-2.88 (m, 2H), 2.80-2.62 (m,1H), 2.52-2.46 (m, 2H), 1.74-1.58 (m, 2H), 0.98-0.90 (m, 3H); LCMS 500.5(M+1)⁺.

EXAMPLE 60

6-[2-Ethyl-4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[2-Ethyl-4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26Steps 1 and 3 using 2-ethyl-piperazine and1-bromo-2-fluoro-4-trifluoromethyl-benzene. ¹H NMR (400 MHz, CD₃OD) δ7.91 (s, 1H), 7.78-7.70 (m, 1H), 7.50-7.40 (m, 1H), 7.36-7.28 (m, 2H),7.10-6.99 (m, 1H), 4.12 (t, 1H), 4.00-3.80 (m, 2H), 3.50-3.22 (m, 3H),3.20-3.15 (m, 1H), 3.14-3.05 (m, 1H), 2.75-2.50 (m, 2H), 2.45 (q, 2H),1.72-1.50 (m, 2H), 1.01-0.95 (m, 3H); LCMS 500.5 (M+1)⁺.

EXAMPLE 61

6-[4-(3,4-Dichloro-phenyl)-(S)-methyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[4-(3,4-Dichloro-phenyl)-(S)-methyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26Steps 1 and 3 using 2-(S)-methyl-piperazine and4-bromo-1,2-dichloro-benzene. ¹H NMR (400 MHz, CD₃OD) δ 7.88 (s, 1H),7.74-7.68 (m, 1H), 7.41 (t, 1H), 7.28-7.24 (m, 1H), 6.94 (dd, 1H),6.78-6.72 (m, 1H), 4.22-4.14 (m, 1H), 4.13-4.07 (m, 1H), 3.78-3.70 (m,1H), 3.50-3.40 (m, 1H), 3.16-3.04 (m, 2H), 3.02-2.92 (m, 1H), 2.90-2.84(m, 1H), 2.76-2.64 (m, 2H), 2.46-2.32 (m, 2H), 1.02 (d, 3H); LCMS 469.4(M+1)⁺.

EXAMPLE 62

6-[2-(S)-Methyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[2-(S)-Methyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26Steps 1 and 3 using 2-(S)-methyl-piperazine and1-bromo-4-trifluoromethoxy-benzene. ¹H NMR (400 MHz, CD₃OD) δ 7.89 (s,1H), 7.73-7.69 (m, 1H), 7.45-7.40 (m, 1H), 7.11-7.06 (m, 2H), 6.92-6.87(m, 2H), 4.22-4.16 (m, 1H), 4.13-4.07 (m, 1H), 3.78-3.70 (m, 1H),3.51-3.41 (m, 1H), 3.16-3.06 (m, 2H), 3.02-2.92 (m, 1H), 2.86-2.79 (m,1H), 2.73-2.61 (m, 2H), 2.45-2.38 (m, 2H), 1.20 (d, 3H); LCMS 484.5(M+1)⁺.

EXAMPLE 63

6-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-2-(S)-methyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-2-(S)-methyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26Steps 1 and 3 using 2-(S)-methyl-piperazine. ¹H NMR (400 MHz, CD₃OD) δ7.87 (d, 1H), 7.71-7.62 (m, 1H), 7.41-7.32 (m, 2H), 6.68-6.58 (m, 2H),4.23-4.16 (m, 1H), 4.14-4.02 (m, 1H), 3.80-3.69 (m, 1H), 3.66-3.47 (m,1H), 3.43-3.34 (m, 2H), 3.12-3.01 (m, 2H), 2.99-2.80 (m, 2H), 2.45-2.36(m, 2H), 1.20-1.00 (m, 3H); LCMS 486.5 (M+1)⁺.

EXAMPLE 64

6-[3-Ethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[3-Ethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26using 3-ethyl-piperazine-1-carboxylic acid tert-butyl ester and2-bromo-5-trifluoromethyl-pyridine. ¹H NMR (400 MHz, CD₃OD) δ 8.30 (s,1H), 7.80 (s, 1H), 7.69-7.60 (m, 2H), 7.50-7.40 (m, 1H) 6.90-6.80 (m,1H), 4.60-4.50 (m, 1H), 4.43-4.35 (m, 1H), 4.15-4.05 (m, 1H), 3.80 (d,2H), 3.35-3.20 (m, 2H), 3.19-3.10 (m, 1H), 3.10-3.00 (m, 1H), 2.50-2.40(m, 3H), 1.99-1.60 (m, 2H), 1.01-0.93 (m, 3H); LCMS 483.5 (M+1)⁺.

EXAMPLE 65

6-[cis-3,5-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[cis-3,5-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26using 3,5-cis-dimethyl-piperazine-1-carboxylic acid tert-butyl ester and2-bromo-5-trifluoromethyl-pyridine. ¹H NMR (400 MHz, CD₃OD) δ 8.05 (s,1H), 7.51 (s, 1H), 7.40-7.30 (m, 2H), 7.18 (d, 1H) 6.46 (d, 1H),4.35-4.25 (m, 1H), 3.25 (t, 1H), 3.41-3.32 (m, 1H), 3.08-3.02 (m, 2H),2.98-2.88 (m, 1H), 2.86-2.78 (m, 1H), 2.74-2.64 (m, 1H), 2.24-2.16 (m,1H), 2.15-2.08 (m, 2H), 1.03 (d, 3H), 1.02 (d, 3H); LCMS 483.5 (M+1)⁺.

EXAMPLE 66

6-(5-Trifluoromethyl-3,6-dihydro-2H-[2,4]bipyridinyl-1-sulfonyl)-indan-1-carboxylicacid

Step 1

A solution of 2-iodo-5-trifluoromethylpyridine (2.2 g, 8.0 mmol) andpyridyl-4-boronic acid (1.0 g, 8.8 mmol) in MeOH (8 mL) and toluene (30mL) was purged with nitrogen for 5 min followed by addition of Pd(PPh₃)₄(0.2 g) and aqueous 2M Na₂CO₃ (4 mL). The mixture was then heated toreflux for 7 h. After cooling the reaction mixture to room temperature,solids were removed by filtration and the filtrate was concentrated invacuo. The residue was dissolved in EtOAc (20 mL) and washed with brine.The organic solution was concentrated in vacuo and purified by columnchromatography to give the desired compound (0.4 g) as a light yellowpowder.

Step 2

To a solution of the compound from Step 1 (0.23 g, 1.1 mmol) in DMF (10mL) was added benzyl bromide (0.2 g, 1.2 mmol). The mixture was thenheated at 95° C. for 8 h. After cooling the reaction mixture to roomtemperature, ether (500 mL) was added slowly and the mixture was stirredovernight. A light yellow crystalline product was removed by filtrationand dried to give the desired compound (0.2 g).

Step 3

To a solution of the product from Step 2 (0.2 g) in MeOH (10 mL) at −52°C. was added NaBH₄ (0.1 g). The reaction mixture was stirred for 30 min.The reaction mixture was concentrated in vacuo. The residue wasdissolved in ether (10 mL) and washed with water (10 mL). After dryingover anhydrous sodium sulfate, the solvent was removed to give thedesired compound (150 mg) as a yellow solid.

Step 4

To a solution of the product from Step 3 (150 mg) in CH₂Cl₂ (10 mL) at−52° C. was added ethyl chloroformate (0.3 g) dropwise. The mixture wasstirred at 0° C. for 40 min. The reaction mixture was concentrated invacuo. The residue was dissolved in MeOH (10 mL) and heated to refluxfor 1 h. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The residue was dissolved in CH₂Cl₂ (20 mL) andtriethylamine (0.5 mL), and methyl2-(5-chlorosulfonyl-2-methylphenyl)acetate (0.3 g) were added. Afterstirring at room temperature overnight, the mixture was washed withbrine (3×20 mL), dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography to afford the desiredcompound (100 mg) as a white solid.

Step 5

To a solution of the product from Step 4 (100 mg) in THF at 0° C. wasadded a 2M NaOH solution (2 mL) dropwise. The reaction mixture waswarmed to room temperature and stirred until all the starting materialwas consumed. The reaction mixture was concentrated in vacuo. Theresidue was acidified to pH 3 with 2M HCl and extracted with EtOAc. Theorganic solution was dried over Na₂SO₄, the solvent was concentrated invacuo to give the title compound (60 mg). ¹H NMR (400 MHz, CD₃OD) δ 8.77(s, 1H), 8.04-8.00 (m, 1H), 7.88 (s, 1H), 7.73-7.64 (m, 2H), 7.47 (d,1H) 6.78 (s, 1H), 4.13 (t, 1H), 3.85-3.81 (m, 1H), 3.36-3.27 (m, 2H),3.14-3.05 (m, 2H), 3.04-2.93 (m, 1H), 2.75-2.67 (m, 2H), 2.42 (q, 2H);LCMS 452.5 (M+1)⁺.

EXAMPLE 67

6-[4-(5-Trifluoromethyl-pyridin-2-yl)-[1,4]diazepane-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[4-(5-trifluoromethyl-pyridin-2-yl)-[1,4]diazepane-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 23using [1,4]diazepane and 2-bromo-5-trifluoromethyl-pyridine. ¹H NMR (400MHz, CD₃OD) δ 8.26 (s, 1H), 7.81 (s, 1H), 7.66-7.56 (m, 2H), 7.25 (d,1H), 6.65 (d, 1H), 4.06 (t, 1H), 3.92-3.86 (m, 1H), 3.84-3.76 (m, 1H),3.75-3.70 (m, 1H), 3.54-3.44 (m, 2H), 3.38-3.24 (m, 3H), 3.10-3.02 (m,1H), 2.98-2.88 (m, 1H), 2.48-2.36 (m, 2H), 1.96-1.88 (m, 2H); LCMS 469.5(M+1)⁺.

EXAMPLE 68

6-[trans-2,6-(S,S)-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[trans-2,6-(S,S)-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26Steps 1 & 3 using 2,6-(S,S)-dimethyl-piperazine and2-bromo-5-trifluoromethyl-pyridine. ¹H NMR (mixture of diastereomers˜1:1, 400 MHz, CD₃OD) δ 8.25 (s, 1H), 8.24 (s, 1H) 7.95 (s, 1H), 7.90(s, 1H), 7.70-7.60 (m, 4H), 7.35 (d, 1H) 7.25 (d, 1H), 6.70 (d, 1H) 6.50(d, 1H), 4.30-4.19 (m, 4H), 4.15 (t, 1H) 4.01 (t, 1H), 3.80-3.60 (m,4H), 3.62-3.52 (m, 2H), 3.43-3.25 (m, 2H), 3.15-2.80 (m, 4H), 2.25-2.15(m, 4H), 1.38 (d, 6H), 1.30 (d, 6H); LCMS 483.8 (M+1)⁺.

EXAMPLE 69

6-[trans-3,5-(S,S)Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[trans-3,5-(S,S)-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure described in Example 26using 3,5-(S,S)-dimethyl-piperazine-1-carboxylic acid tert-butyl esterand 2-bromo-5-trifluoromethyl-pyridine. ¹H NMR (400 MHz, CD₃OD) δ8.38-8.30 (m, 1H), 7.90 (s, 1H), 7.80-7.65 (m, 2H), 7.45 (d, 1H) 6.65(d, 1H), 4.65-4.55 (m, 1H), 4.43-4.32 (m, 2H), 4.20-4.10 (m, 1H)3.70-3.58 (m, 3H), 3.20-3.10 (m, 1H), 3.09-3.00 (m, 1H), 2.58-2.38 (m,2H), 1.05 (d, 3H), 1.02 (d, 3H); LCMS 483.5 (M+1)⁺.

EXAMPLE 70

6-[cis-2,6-Dimethyl-4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[cis-2,6-dimethyl-4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure outlined in Example 63using 3,5-cis-dimethyl-piperazine. ¹H NMR (400 MHz, CD₃OD) δ 7.87 (s,1H), 7.70 (dd, 1H), 7.38-7.34 (m, 2H), 6.62 (s, 1H), 6.59 (d, 1H),4.26-4.22 (m, 1H), 4.16-4.10 (m, 1H), 4.08 (t, 1H), 3.47 (d, 2H),3.10-3.02 (m, 1H), 2.97-2.88 (m, 3H), 2.40 (q, 2H), 1.42 (d, 3H), 1.40(d, 2H).

EXAMPLE 71

6-[4-(4-Trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure outlined in Example 26using 1-(4-trifluoromethoxy-phenyl)-piperazine. ¹H NMR (400 MHz, CDCl₃)

7.85 (s, 1H), 7.66 (dd, 1H), 7.41 (d, 1H), 7.12 (d, 2H), 6.95 (d, 2H),4.15 (t, 1H), 3.40-3.08 (m, 9H), 3.04-2.96 (m, 1H), 2.56-2.42 (m, 2H);LCMS 471.5 (M+1)⁺.

EXAMPLE 72

6-[2-Ethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[2-ethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure outlined in Example 26Step 1 (using 2-ethyl-piperazine and2-chloro-5-trifluoromethyl-pyridine) and Step 3 (using3-ethyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine). ¹H NMR (400 MHz,CDCl₃)

8.32 (s, 1H), 7.92 (s, 1H), 7.72 (t, 1H), 7.58 (t, 1H), 7.36-7.31 (m,1H), 6.54-6.48 (m, 1H), 4.20-4.05 (m, 3H), 3.99-3.93 (m, 1H), 3.85-3.73(m, 1H), 3.32-3.20 (m, 1H), 3.16-2.82 (m, 4H), 2.54-2.38 (m, 2H),1.62-1.48 (m, 2H), 0.90 (q, 3H); LCMS 484.0 (M+1)⁺.

EXAMPLE 73

6-[3,3-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[3,3-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure outlined in Example 26using 2,2-dimethyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine. ¹H NMR(400 MHz, CDCl₃)

8.47 (s, 1H), 7.85 (s, 1H), 7.66-7.62 (m, 2H), 7.40 (d, 1H), 6.86 (d,1H), 4.15 (t, 1H), 3.61 (br s, 2H), 3.25-3.12 (m, 3H), 3.05-2.96 (m,1H), 2.92 (s, 2H), 2.57-2.41 (m, 2H), 1.44 (s, 6H); LCMS 483.9 (M+1)⁺.

EXAMPLE 74

6-[4-(3-Chloro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[4-(3-chloro-4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was synthesized according to the procedure outlined in Example 26using 1-(3-Chloro-4-trifluoromethyl-phenyl)-piperazine. ¹H NMR (400 MHz,CDCl₃)

7.83 (s, 1H), 7.65 (d, 1H), 7.47 (d, 1H), 7.41 (d, 1H), 6.86 (d, 1H),6.70 (dd, 1H), 4.17-4.11 (m, 1H), 3.36-3.33 (m, 4H), 3.19-3.10 (m, 5H),3.04-2.96 (m, 1H), 2.54-2.41 (m, 2H); LCMS 489.5 (M+1)⁺.

EXAMPLE 75

Single enantiomer of6-[cis-2,6-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: This single enantiomer of6-[cis-2,6-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was obtained by chiral HPLC (chiralcel OD-H 0.46×15 cm Hex/IPA 96:4(v/v) with 0.1% TFA, flow rate 1 ml/min) separation from the racemate.LCMS 482.1 (M−1)⁻.

EXAMPLE 76

Single enantiomer of6-[cis-2,6-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: This single enantiomer of6-[cis-2,6-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was obtained by chiral HPLC (chiralcel OD-H 0.46×15 cm Hex/IPA 96:4(v/v) with 0.1% TFA, flow rate 1 ml/min) separation from the racemate.LCMS 482.0 (M−1)⁻.

EXAMPLE 77

4-[cis-2,6-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid

Step 1

cis-3,5-Dimethyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine: Thecompound cis-3,5-dimethyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazinewas synthesized according to the procedure described in Example 26 usingcis-2,6 dimethyl piperazine.

Step 2

4-[cis-2,6-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound4-[cis-2,6-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure outlined in Example 79using methyl-4-chlorosulfonyl-2-carboxylate andcis-3,5-dimethyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine obtainedfrom Step 1 above. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (s, 1H), 7.74 (d, 1H),7.61 (dd, 1H), 7.41 (d, 1H), 7.30 (t, 1H), 6.58 (d, 1H), 4.40-4.30 (m,4H), 3.66-3.53 (m, 2H), 3.45-3.35 (m, 1H), 3.31-3.28 (m, 2H), 3.13 (dd,1H), 3.05 (dd, 1H), 1.41 (d, 3H), 1.40 (dd, 3H); LCMS 483.8 (M+1)⁺.

EXAMPLE 78

4-[2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound4-[2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure outlined in Example 26using 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl esterand 2-chloro-5-trifluoromethyl-pyridine. ¹H NMR (400 MHz, CD₃OD) δ 8.33(s, 1H), 7.94 (s, 1H), 7.79 (dd, 1H), 7.72 (dd, 1H), 7.46 (d, 1H), 6.79(d, 1H), 4.40-4.30 (m, 3H), 3.17-3.09 (m, 3H), 3.05-2.97 (m, 2H), 2.43(q, 2H), 1.60-1.36 (m, 4H); LCMS 482.5 (M+1)⁺.

EXAMPLE 79

4-[cis-2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid

Step 1

1,2-Bis(bromomethyl)-3-nitrobenzene: A 1 liter flask was charged with1,2-dimethyl-3-nitrobenzene (20 g, 0.13 mol), N-bromosuccinimide (50 g,0.28 mol), azobis(isobutyronitrile) (5 g, 3.0 mmol), and 200 mL ofdichloromethane. This was irradiated with a 120 watt floodlamp to affectgentle reflux under nitrogen for 18 hours. The mixture was then cooledand precipitated succinimide was removed by filtration. The filtrate wasconcentrated and the residue was purified by chromatography on silica(5%-50% CH₂Cl₂ in hexanes) to give 2.6 g white solid (64%).

Step 2

Dimethyl-4-nitroindane-2,2-dicarboxylate: To a solution stirred undernitrogen at room temperature, to 5.0 mL methanol in 15.0 mL ether wasadded 60% sodium hydride (0.84 g, 0.021 mol) in small portions. Afterthe addition was complete, the nearly clear and colorless solution wasstirred for 5 minutes. To it was then added 1.3 g dimethyl malonate,giving a slightly cloudy colorless solution. To this was rapidly added asuspension of 3.1 g 1,2-bis(bromomethyl)3-nitrobenzene, which immediategave a precipitate suspended in a dark green solution. This was removedby filtration and the filtrate was concentrated. The residue waspurified on silica (20%-100% CH₂Cl₂ in hexanes) to give 1.93 g off-whitesolid (67%).

Step 3

Methyl-4-nitroindane-2-carboxylate: A mixture ofdimethyl-4-nitroindane-2,2-dicarboxylate (4.84 g, 0.0167 mol), lithiumchloride (0.84 g, 0.0198 mol), 1.1 mL water, and 18 mL dimethylsulfoxidewas heated to 160° C. under nitrogen for two hours. It was then allowedto cool and the dimethylsulfoxide was removed under high vacuum. Theresidue was purified on silica (10%-100% CH₂Cl₂ in hexanes) to give 2.5g white solid (65%).

Step 4

Methyl-4-aminoindane-2-carboxylate: A mixture ofmethyl-4-nitroindane-2-carboxylate (2.4 g, 0.11 mol) and 10% palladiumon carbon (1.1 g, 0.01 mol) in ethyl acetate (15 mL) was shaken under 55PSI hydrogen for 1 hour. It was then filtered and the filtrate wasconcentrated to give 2.07 g white solid (100%).

Step 5

Methyl 4-chlorosulfonyl-indan-2-carboxylate: A mixture ofmethyl-4-aminoindane-2-carboxylate (2.5 g, 0.013 mol), 12.5 mLacetonitrile, and 12.5 mL H₂O was cooled to −5° C. in an ice-salt bath.To this was added 2.6 mL concentrated HCl (0.014 mol). To this was addeddropwise over 20 minutes a solution of 1.0 g sodium nitrite (0.021 mol)in 5 mL water. After the addition was complete the solution was stirredfor 20 minutes. It was then transferred to a jacketed addition funnelcooled with ice water. The solution was added dropwise to a solutionstirred under nitrogen at 55° C. of 4.2 g potassium thioxanthate (0.026mol) in 20 mL H₂O. As the addition took place, a dark layer rose to thetop of the diazonium ion solution which was not added. After theaddition was complete the mixture was stirred at 55° C. for 30 minutes,then was allowed to cool and was extracted with 40 mL ethyl acetate. Theorganic layer was dried (MgSO₄) and concentrated. The residue was loadedon 80 mL silica gel which was slurry-packed in hexanes. This was elutedwith 100 mL hexanes, then 1%-50% CH₂Cl₂ in hexanes in 50 mL fractions togive 1.3 g amber oil (33%).

A mixture of 3.6 g of the above compound in 30 mL CCl₄ and 10 mL H₂O wasvigorously stirred and cooled to 3 C. Chlorine gas was bubbled throughat such a rate that the temperature stayed below 10° C. After conversionwas complete, the phases were separated and the aqueous layer wasextracted with CH₂Cl₂. The combined organic layers were dried (MgSO₄)and concentrated to give 4.0 g yellow oil (100%).

Step 6

4-[cis-2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-methylester: A mixture of methyl 4-chlorosulfonyl-indan-2-carboxylate (2.13 g,0.0078 mol) obtained from Step 6,cis-3,5-dimethyl-1-(4-trifluoromethoxy-phenyl)-piperidine (3.0 g, 0.0109mol) obtained from Example 51, 20 mL acetonitrile, and 3.0 g K₂CO₃(0.0217 mol) was heated to 60° C. under nitrogen with stirring for 20hours. It was then filtered and the filtrate was concentrated. Theresidue was purified by chromatography on silica (5%-50% EtOAc inhexanes) to give 2.64 g viscous yellow oil (66%).

Step 7

4-[cis-2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: To a solution of4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-methylester (2.64 g, 0.0052 mol) in the minimum amount of THF (ca 15 mL) wasadded a solution of 0.14 g LiOH (0.0057 mol) in the minimum amount ofwater (ca 2.5 mL). This was capped and stirred at room temperature for12 hours. Examination by HPLC showed the reaction was 85% complete so anadditional 0.020 g LiOH (0.125 eq total) was added and stirring wascontinued for 3 hours. It was then concentrated to remove THF andpartitioned between EtOAc and water. The aqueous layer was treated with0.54 mL conc. HCl. It was then extracted with ethyl acetate. The organiclayer was dried (MgSO₄) and concentrated to give 2.38 g yellow amorphoussolid (93%).

EXAMPLE 80

A single enantiomer of Example 79 was obtained by chiral HPLC (chiralpakASH 0.46×15 cm Hex/IPA 94:6 (v/v) with 0.1% TFA, flow rate 1 ml/min)separation from the racemate. LCMS 497.1 (M−1)⁻.

EXAMPLE 81

A single enantiomer of Example 79 was obtained by chiral HPLC (chiralpakASH 0.46×15 cm Hex/IPA 94:6 (v/v) with 0.1% TFA, flow rate 1 ml/min)separation from the racemate. LCMS 497.1 (M−1)⁻.

EXAMPLE 82

4-[4-(3-Chloro-4-trifluoromethyl-phenyl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound4-[4-(3-chloro-4-trifluoromethyl-phenyl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized by coupling methyl-4-chlorosulfonyl-2-carboxylateobtained from Example 79 Step 5 and1-(3-chloro-4-trifluoromethyl-phenyl)-cis-3,5-dimethyl-piperazine usedin Example 50. ¹H NMR (400 MHz, CD₃OD) δ 7.70 (d, 1H), 7.50-7.42 (m,2H), 7.32 (t, 1H), 6.94 (d, 1H) 6.82 (m, 1H), 4.25-4.18 (m, 1H),4.11-4.01 (m, 1H) 3.62-3.52 (m, 4H), 3.41-3.32 (m, 1H), 3.29-3.24 (m,2H), 3.03 (dd, 1H), 2.94 (m, 1H) 1.45 (d, 3H), 1.43 (d, 3H); LCMS 517.0(M+1)⁺.

EXAMPLE 83

4-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound4-[4-(3-fluoro-4-trifluoromethyl-phenyl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized in a similar fashion as described in Example 82. ¹HNMR (400 MHz, CD₃OD) δ 7.20 (d, 1H), 7.40 (d, 1H), 7.44-7.32 (m, 2H),6.74 (s, 1H) 6.72-6.67 (m, 1H), 4.26-4.20 (m, 1H), 4.10-4.02 (m, 1H)3.66-3.58 (m, 2H), 3.54 (d, 2H), 3.42-3.34 (m, 2H), 3.30-3.25 (m, 1H),3.01 (dd, 1H), 2.94 (m, 1H) 1.46 (d, 3H), 1.40 (d, 3H); LCMS 500.5(M+1)⁺.

EXAMPLE 84

5-[cis-2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound5-[2,6-cis-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure outlined in Example 1using indane-2-carboxylic acid methyl ester andcis-3,5-dimethyl-1-(4-trifluoromethoxy-phenyl)-piperazine (made byprocedure outlined in Example 26 step 1 using 2,6-cis-dimethylpiperazine and 1-bromo-4-trifluoromethoxy-benzene). ¹H NMR (400 MHz,CD₃OD)

7.72 (s, 1H), 7.66 (d, 1H), 7.37 (d, 1H), 7.09 (d, 2H), 6.87 (d, 2H),4.22-4.12 (m, 2H), 3.41-3.25 (m, 7H), 2.64-2.58 (m, 2H), 1.46 (d, 6H);LCMS 499.5 (M+1)⁺.

EXAMPLE 85

6-[4-(4-Difluoromethoxy-3-methyl-phenyl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid

Step 1

1-Difluoromethoxy-2-methyl-4-nitrobenzene: To a solution of2-methyl-4-nitrophenol (14 g, 91.50 mmol) in dimethylformamide (120 mL)and water (25 mL) was added Cs₂CO₃ (41.8 g, 128.22 mmol), and sodium2-chloro-2,2-difluoroacetate (32 g, 209.84 mmol). The resulting solutionwas stirred for 20 minutes at room temperature, then for an additional 3hours at 100° C. The reaction solution was cooled to room temperaturebefore the addition of 100 ml of H₂O. The resulting solution wasextracted with EtOAc (4×100 ml) and the combined organic layers werewashed with H₂O (2×150 mL), dried over Na₂SO₄, concentrated in vacuo.The residue was purified by silica gel column chromatography to provide16 g (86%) of 1-(difluoromethoxy)-2-methyl-4-nitrobenzene.

Step 2

4-Amino-1-difluoromethoxy-2-methyl-benzene: To a solution of1-(difluoromethoxy)-2-methyl-4-nitrobenzene (10 g, 48.28 mmol) inethanol (150 mL) and water (150 mL) was added iron powder (12 g, 214.29mmol). Acetic acid (cat. amount) was added dropwise with stirring andthe reaction mixture was heated at reflux for 20 minutes. The mixturewas cooled to room temperature and solids were removed by filtration.Volatiles were removed in vacuo and the aqueous solution was extractedwith EtOAc (3×150 mL). The combined organic layers were dried overNa₂SO₄ and concentrated in vacuo to provide 8 g (95%) of4-amino-1-difluoromethoxy-2-methyl-benzene.

Step 3

4-Bromo-1-difluoromethoxy-2-methyl-benzene: To a stirred solution of4-amino-1-difluoromethoxy-2-methyl-benzene (5 g, 28.90 mmol) in HBr (20mL) and water (20 mL) at 0° C. was added a solution of sodium nitrite(2.07 g, 30.00 mmol) in H₂O (10 ml) dropwise over a period of 20minutes. After the addition was complete, the reaction mixture wasstirred for 30 minutes at 0° C. Copper (I) bromide (4 g, 27.87 mmol) wasthen added and the mixture was heated at 60° C. for 30 minutes. Theresulting solution was extracted with EtOAc (3×50 mL) and the combinedorganic layers washed with H₂O (1×20 mL), dried over Na₂SO₄ andconcentrated to provide 2.5 g (37%) of4-bromo-1-(difluoromethoxy)-2-methylbenzene.

Step 4

1-(4-Difluoromethoxy-3-methyl-phenyl)-cis-3,5-dimethyl-piperazine: To4-bromo-1-(difluoromethoxy)-2-methylbenzene (2.36 g, 10.00 mmol) intoluene (50 mL) was added cis-2,6-dimethylpiperazine (5 g, 58.14 mmol),Pd(OAc)₂ (120 mg, 0.53 mmol), BINAP (380 mg, 0.61 mmol), and t-BuOK (2.2g, 19.64 mmol). The resulting solution was stirred for 4 hours at 80° C.The solution was cooled to room temperature and washed with H₂O (2×50mL), dried over Na₂SO₄, concentrated, and purified by silica gel columnchromatography (10:1 CH₂Cl₂/MeOH) to give 1.1 g (41%) of1-(4-(difluoromethoxy)-3-methylphenyl)-3,5-dimethylpiperazine.

Step 5

6-[4-(4-Difluoromethoxy-3-methyl-phenyl)-2,6-dimethyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[4-(4-difluoromethoxy-3-methyl-phenyl)-2,6-dimethyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid was prepared according to the procedure outlined in Example 1 usingindane-1-carboxylic acid methyl ester. ¹H NMR (CD₃OD) δ 7.82 (s, 1H),7.72 (dd, 1H), 7.39 (dd, 1H), 6.93 (d, 1H), 6.72 (s, 1H), 6.65 (d, 1H),6.60 (t, 1H), 4.15 (m, 2H), 3.69 (s, 2H), 3.22 (d, 2H), 3.09 (m, 1H),2.97 (m, 1H) 2.58 (dd, 1H), 2.48 (dd, 1H), 2.42 (m, 2H), 2.19 (s, 3H),1.45 (d, 6H).

EXAMPLE 86

6-[2,3-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[2,3-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was prepared according to the method described in the preparationof Example 23. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 8.33 (s, 1H), 7.85 (d,1H), 7.62 (d, 1H), 7.56 (t, 1H), 7.29 (d, 1H), 6.43 (dd, 1H), 4.37 (m,1H), 4.11 (m, 3H), 3.20 (m, 2H), 3.08 (m, 3H), 2.45 (m, 2H), 1.41 (dd,3H, 1.18 (dd, 3H).

EXAMPLE 87

{5-[2,3-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid: The compound{5-[2,3-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid was prepared according to the method described in the preparationof Example 37. ¹H NMR (400 MHz, CDCl₃), δ (ppm): 8.29 (s, 1H), 8.28 (s,1H), 7.76 (m, 2H), 7.59 (s, 1H), 7.48 (d, 1H), 6.34 (d, 1H), 4.39 (m,1H), 3.98 (m, 2H), 3.88 (s, 2H), 3.37 (m, 1H), 3.25 (m, 1H), 3.15 (m,1H), 1.44 (d, 3H), 1.18 (d, 3H).

EXAMPLE 88

{6-[cis-2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid: The compound{6-[cis-2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid was synthesized according to the procedure outlined in Example 34using cis-3,5-dimethyl-1-(4-trifluoromethoxy-phenyl)-piperazine fromExample 51. ¹H NMR (400 MHz, CD₃OD)

7.89 (s, 1H), 7.71 (d, 1H), 7.52 (dd, 1H), 7.44 (d, 1H), 7.05 (d, 2H),6.84 (d, 2H), 6.58 (d, 1H), 5.02 (s, 2H), 4.23-4.19 (m, 2H), 3.27 (d,2H), 2.55 (dd, 2H), 1.46 (d, 6H); LCMS 512.6 (M+1)⁺.

EXAMPLE 89

4-[4-(5-Trifluoromethoxy-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid. The compound4-[4-(5-Trifluoromethoxy-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was prepared according to the procedure outlined in Example 79using 1-(5-trifluoromethoxy-pyridin-2-yl)-piperazine. ¹H NMR (CD₃OD) δ8.02 (d, 1 H), 7.60 (d, 1 H), 7.51 (d, 1 H), 7.46 (m, 1 H), 7.38 (t, 1H), 6.82 (d, 1 H), 3.62 (m, 3 H), 3.55 (d, 2 H), 3.16 (m, 8 H).

EXAMPLE 90

{6-[4-(4-Trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid.{6-[4-(4-Trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid methyl ester was prepared from1-(4-trifluoromethoxy-phenyl)-piperazine following the proceduresoutlined in Example 34. A mixture of{6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid methyl ester (45 mg, 0.09 mmol), 1M LiOH (2 mL), tetrahydrofuran (6mL), and methanol (2 mL) was stirred at rt for 3 h. The reaction waspoured into 1M HCl (50 mL) and extracted with ethyl acetate (40 mL×2).The combined organic extracts were dried, filtered, and concentrated togive{6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid: ¹H NMR (400 MHz, DMSO-d6):

7.89 (s, 1H), 7.77 (d, 1H), 7.63 (d, 1H), 7.38 (d, 1H), 7.14 (d, 2H),6.93 (d, 2H), 6.61 (d, 1H), 5.19 (s, 2H), 3.23-3.15 (m, 4H), 3.03-2.95(m, 4H); MS (ESI): 483.7 (M+H).

EXAMPLE 91

{6-[4-(4-Trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-aceticacid. Triethylsilane (0.13 mL, 0.77 mmol) was added to a solution of{6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-aceticacid methyl ester (82 mg, 0.16 mmol) and trifluoroacetic acid (4 mL) atrt. After 1 h, more triethylsilane (0.2 mL, 1.2 mmol) was added. Afteran additional 4 h, the reaction was poured into 1.2 M NaOH (50 mL) andextracted with CH₂Cl₂ (3×30 mL). The combined organic extracts weredried, filtered, concentrated and purified by silica gel chromatography(4:1→3:2; hexanes:ethyl acetate) to give{6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-aceticacid methyl ester: MS (ESI): 500.1 (M+H).{6-[4-(4-Trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-aceticacid methyl ester was hydrolyzed following the procedure outlined inExample 1 Step 2 to give{6-[4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-2,3-dihydro-indol-1-yl}-aceticacid: ¹H NMR (400 MHz, DMSO-d6):

7.24 (d, 1H), 7.19 (d, 2H), 6.98 (d, 2H), 6.93 (d, 1H), 6.68 (s, 1H),4.05 (s, 2H), 3.57 (t, 2H), 3.24-3.17 (m, 4H), 3.03 (t, 2H), 3.00-2.94(m, 4H); MS (ESI): 486.1 (M+H).

EXAMPLE 92

4-[4-(4-Chloro-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid.The compound4-[4-(4-chloro-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acidwas prepared from 1-(4-chloro-phenyl)-piperazine and4-chlorosulfonyl-indan-2-carboxylic acid methyl ester following theprocedure outlined in Example 79. ¹H NMR (400 MHz, DMSO-d6):

7.58 (d, 1H), 7.56 (d, 1H), 7.43 (t, 1H), 7.23 (d, 2H), 6.92 (d, 2H),3.50-3.41 (m, 2H), 3.40-3.29 (m, 1H), 3.28-3.13 (m, 6H), 3.12-3.04 (m,4H); MS (ESI): 420.9 (M+H).

EXAMPLE 93

4-[2-(S)-Methyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid. The compound4-[2-(S)-Methyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was prepared from3-(S)-methyl-1-(4-trifluoromethoxy-phenyl)-piperazine and4-chlorosulfonyl-indan-2-carboxylic acid methyl ester following theprocedure outlined in Example 79. ¹H NMR (400 MHz, DMSO-d6):

7.65 (d, 1H), 7.53 (d, 1H), 7.38 (t, 1H), 7.18 (d, 2H), 6.98-6.92 (m,2H), 4.15-4.00 (m, 1H), 3.60-3.12 (m, 9H), 2.83-2.75 (m, 1H), 2.64-2.50(m, 1H), 1.18 (d, 3H); MS (ESI): 485.3 (M+H).

EXAMPLE 94

4-[2-(S)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid. The compound4-[2-(S)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was prepared from3-(S)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine and4-chlorosulfonyl-indan-2-carboxylic acid methyl ester following theprocedure outlined in Example 79. ¹H NMR (400 MHz, DMSO-d6):

8.38 (s, 1H), 7.82-7.76 (m, 1H), 7.65 (d, 1H), 7.52 (d, 1H), 7.37 (t,1H), 6.93-6.88 (m, 1H), 4.35-4.18 (m, 2H), 4.18-4.02 (m, 1H), 3.60-3.46(m, 1H), 3.45-3.10 (m, 7H), 2.97-2.80 (m, 1H), 1.06-1.01 (m, 3H); MS(ESI): 470.0 (M+H).

EXAMPLE 95

4-[cis-2,6-Dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid

Step 1

cis-3,5-Dimethyl-1-(4-trifluoromethoxy-benzyl)-piperazine: To a solutionof 4-(trifluoromethoxy)-benzaldehyde (776 uL, 4.38 mmol) in methylenechloride (30 mL) was added cis-2,6-dimethyl piperazine (1.0 g, 8.77mmol). After 1 hour sodium triacetoxy borohydride (2.45 g, 8.77 mmol)was added to the mixture. The solution was stirred at room temperaturefor an additional 4 hours. The reaction was concentrated in vacuo,diluted with ethyl acetate and extracted with 1N HCl (2×50 mL). Theaqueous layer was then neutralized with NaOH and extracted with ethylacetate (3×50 mL). The organic layer was dried (Na₂SO₄) and concentratedto provide cis-3,5-dimethyl-1-(4-trifluoromethoxy-benzyl)-piperazine(1.01 g, 80%). ¹H NMR (400 MHz, CD₃OD) δ 7.42 (d, 2H), 7.23 (d, 2H),3.54 (s, 2H), 2.98-2.88 (m, 2H), 2.82-2.74 (m, 2H), 1.69 (t, 2H), 1.05(d, 6H); LCMS 289.5 (M+1)⁺.

Step 2

4-[cis-2,6-Dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure in Example 79 usingcis-3,5-dimethyl-1-(4-trifluoromethoxy-benzyl)-piperazine. ¹H NMR (400MHz, CD₃OD) δ 7.74-7.64 (m, 4H), 7.47 (d, 1H), 7.39-7.28 (m, 2H), 4.42(s, 2H), 4.21-2.18 (m, 2H), 3.50-3.34 (m, 5H), 3.33-3.19 (m, 4H), 1.56(d, 6H); LCMS 497.5 (M+1)⁺.

EXAMPLE 96

4-[cis-2,6-Dimethyl-4-(4-trifluoromethyl-benzyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound4-[cis-2,6-dimethyl-4-(4-trifluoromethyl-benzyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure in Example 95, using4-(trifluoromethyl)-benzaldehyde. ¹H NMR (400 MHz, CD₃OD) δ 7.78-7.62(m, 5H), 7.47 (d, 1H), 7.32 (t, 1H), 4.41 (s, 2H), 4.21-2.15 (m, 2H),3.52-3.36 (m, 5H), 3.34-3.22 (m, 4H), 1.52 (d, 6H); LCMS 497.5 (M+1)⁺.

EXAMPLE 97

4-[4-(4-Trifluoromethyl-benzyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound4-[4-(4-trifluoromethyl-benzyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure in Example 95, usingpiperazine and 4-(trifluoromethyl)-benzaldehyde. ¹H NMR (400 MHz, CD₃OD)δ 7.82-7.73 (m, 4H), 7.62 (d, 1H), 7.54 (d, 1H), 7.38 (t, 1H), 4.47 (s,2H), 3.54-3.48 (m, 5H), 3.46-3.35 (m, 2H), 3.32-3.22 (m, 6H); LCMS 469.5(M+1)⁺.

EXAMPLE 98

4-[4-(4-Trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound4-[4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure in Example 95, usingpiperazine. ¹H NMR (400 MHz, CD₃OD) δ 7.70-7.60 (m, 3H), 7.54 (d, 1H),7.42-7.33 (m, 3H), 4.41 (s, 2H), 3.54-3.48 (m, 5H), 3.46-3.35 (m, 2H),3.32-3.22 (m, 6H); LCMS 484.9 (M+1)⁺.

EXAMPLE 99

4-[cis-2,6-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid

Step 1

2-Bromo-pyridin-5-ol: To a solution of 6-bromopyridin-3-ylboronic acid(9.5 g, 43.48 mmol) in THF (180 mL) was added oxydol (8.8 g, 98.35 mmol)dropwise with stirring at 0° C. After 10 minutes, acetic acid (5.6 g,93.33 mmol) was added dropwise with stirring at 0° C. The resultingsolution was stirred overnight at room temperature. The product wasprecipitated after addition of NaHSO₃ and NaHCO₃. The resulting solutionwas extracted with EtOAc (3×80 mL) and the organic layers were combinedand dried over MgSO₄. The solvent was concentrated to give 7 g (88%) of2-bromo-pyridin-5-ol.

Step 2

2-Bromo-5-trifluoromethoxy-pyridine: Into a 50 mL sealed tube was placed6-bromopyridin-3-ol (2.5 g, 14.37 mmol), perchloromethane (6.6 g, 42.86mmol) and antimony pentafloride (101 g, 465.44 mmol). The resultingsolution was heated at 150° C. for 8 hours. After cooling to roomtemperature, the reaction mixture was poured into ice water andneutralized with saturated KOH. The resulting solution was extractedwith EtOAc (100 ml×2) and the organic layers combined and dried overMgSO₄. The solvent was concentrated to afford 0.1 g (2.9%) of2-bromo-5-(trifluoromethoxy)pyridine.

Step 3

cis-3,5-Dimethyl-1-(5-trifluoromethoxy-pyridin-2-yl)-piperazine: Thecompound cis-3,5-Dimethyl-1-(5-trifluoromethoxy-pyridin-2-yl)-piperazinewas synthesized according to the procedure described in Example 26 using2-bromo-5-(trifluoromethoxy)pyridine and cis-2,6-dimethylpypiperazine.

Step 4

4-[cis-2,6-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound4-[cis-2,6-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure in Example 79. ¹H NMR(400 MHz, CD₃OD) δ 7.98 (s, 1H), 7.71 (d, 1H), 7.47-7.42 (m, 2H), 7.33(t, 1H), 6.77 (d, 1H), 4.24-4.18 (m, 1H), 4.12-4.00 (m, 3H), 3.56-3.52(m, 2H), 3.41-3.25 (m, 3H), 3.03 (dd, 1H), 2.95 (dd, 1H), 1.39 (d, 6H);LCMS 500.5 (M+1)⁺.

EXAMPLE 100

{5-[cis-2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid: The compound{5-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid was synthesized according to the procedure in Example 47, usingcis-2,6-dimethylpiperazine and 1-bromo-4-trifluoromethoxy benzene. ¹HNMR (400 MHz, CD₃OD) δ 8.46 (s, 1H), 7.94 (d, 1H), 7.84 (d, 1H), 7.73(s, 1H), 7.04 (d, 2H), 6.81 (d, 2H), 4.24-4.20 (m, 2H), 3.91 (s, 2H),3.27-3.25 (m, 2H), 2.56 (dd, 2H), 1.47 (d, 6H); LCMS 528.9 (M+1)⁺.

EXAMPLE 101

4-[cis-2,6-Dimethyl-4-(4-trifluoromethylsulfanyl-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound4-[cis-2,6-dimethyl-4-(4-trifluoromethylsulfanyl-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure in Example 26, usingcis-2,6-dimethylpiperazine and1-bromo-4-(trifluoromethylsulfanyl)-benzene. ¹H NMR (400 MHz, CD₃OD) δ7.71 (d, 1H), 7.50-7.44 (m, 3H), 7.33 (t, 1H), 6.91 (d, 2H), 4.22-4.19(m, 1H), 4.06-4.02 (m, 1H), 3.62-3.50 (m, 4H), 3.41-3.22 (m, 3H), 2.91(dd, 1H), 2.82 (dd, 1H), 1.45 (d, 6H); LCMS 514.9 (M+1)⁺.

EXAMPLE 102

4-[4-(-Trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound4-[4-(-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure in Example 26 using1-bromo-4-(trifluoromethoxy)-benzene. ¹H NMR (400 MHz, CD₃OD) δ 7.61 (d,1H), 7.52 (d, 1H), 7.38 (t, 1H), 7.10 (d, 2H), 6.96 (d, 2H), 3.59-3.54(m, 2H), 3.42-3.27 (m, 3H), 3.25-3.18 (m, 8H); LCMS 470.9 (M+1)⁺.

EXAMPLE 103

6-[4-(2,4-Dichloro-phenyl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[4-(2,4-dichloro-phenyl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indan-1-carboxylicacid was prepared followed the procedure for Example 26. ¹H NMR (400MHz, CDCl₃), δ 7.90 (s, 1H), 7.72 (d, 1H), 7.36 (d, 1H), 7.35 (s, 1H),7.10 (d, 1H), 6.80 (d, 1H), 4.25 (m, 1H), 4.11 (m, 2H), 3.17 (m, 1H),2.99 (m, 3H), 2.64 (dd, 1H), 2.47 (m, 3H), 1.55 (d, 6H).

EXAMPLE 104

6-[cis-2,6-Dimethyl-4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid: The compound6-[cis-2,6-dimethyl-4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-1-carboxylicacid was prepared followed the procedure for Example 26. ¹H NMR (400MHz, CDCl₃), δ 7.89 (s, 1H), 7.77 (d, 1H), 7.42 (d, 2H), 7.32 (d, 1H),6.78 (d, 2H), 4.26 (m, 1H), 4.11 (m, 2H), 3.36 (m, 2H), 3.09 (m, 1H),2.94 (m, 1H), 2.83 (m, 1H), 2.77 (m, 1H), 2.44 (m, 2H), 1.44 (d, 6H).

EXAMPLE 105

4-[cis-2,6-Dimethyl-4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound4-[cis-2,6-Dimethyl-4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was prepared followed the procedure for Example 79. ¹H NMR (400MHz, CDCl₃) δ 7.73 (s, 1H), 7.45 (d, 2H), 7.40 (d, 1H), 7.30 (d, 1H),6.84 (d, 2H), 4.23 (m, 1H), 4.06 (m, 1H), 3.58 (m, 2H), 3.39 (m, 3H),3.28 (m, 2H), 2.92 (dd, 1H), 2.83 (dd, 1H), 1.48 (dd, 6H).

EXAMPLE 106

4-[4-(4-tert-Butyl-phenyl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indan-2-carboxylicacid

Step 1

1-(4-tert-Butyl-phenyl)-cis-3,5-dimethyl-piperazine: To a solution ofcis-2,6-dimethylpiperazine (1 g, 8.7 mmol) in toluene (35 mL) was added4-(tert-butyl)bromobenzene (1.86 g, 8.7 mmol), followed by BINAP (0.81g, 1.3 mmol) and t-BuONa (1.5 g, 15.6 mmol) in one portion each. Theresulting mixture was degassed twice. To the mixture was added Pd₂(dba)₃(0.79 g, 0.87 mmol) in one portion and the mixture was heated to 100° C.overnight. The reaction mixture was cooled to room temperature andextracted with ethyl acetate (3×100 mL), washed with water (1×100 mL),and brine (1×50 mL), dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (0-20% MeOH indichloromethane) to afford 0.8 g1-(4-tert-Butyl-phenyl)-cis-3,5-dimethyl-piperazine. ¹H NMR (400 MHz,CDCl₃) δ 7.29-7.26 (m, 2H), 6.88-6.86 (m, 2H), 3.49-3.46 (m, 2H),3.08-3.00 (m, 2H), 2.33-2.27 (m, 2H), 2.15 (1H, br), 1.29 (s, 9H), 1.13(d, 6H).

Step 2

4-[4-(4-tert-Butyl-phenyl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indan-2-carboxylicacid

The compound4-[4-(4-tert-butyl-phenyl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indan-2-carboxylicacid was synthesized according to the procedure outlined in Example 79using indane-2-carboxylic acid methyl ester and1-(4-tert-Butyl-phenyl)-cis-3,5-dimethyl-piperazine obtained from Step 1above. ¹H NMR (400 MHz, CD₃OD)

7.71 (d, 1H), 7.47 (d, 1H), 7.34 (t, 1H), 7.24 (d, 2H), 6.81 (d, 2H),4.16-4.14 (m, 1H), 4.02-4.00 (m, 1H), 3.54 (d, 2H), 3.34-3.26 (m, 5H),2.67 (dd, 1H), 2.59 (dd, 1H), 1.51 (d, 3H), 1.50 (d, 3H), 1.26 (s, 9H).

EXAMPLE 107

4-[4-(4-Chloro-5-trifluoromethyl-pyridin-2-yl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indan-2-carboxylicacid

Step 1

(4,6-Dichloro-pyridin-3-yl)-methanol: To lithium aluminum hydride (2.4g, 64 mmol) and aluminum chloride (17 g, 128 mmol) in Et₂O (200 mL) at0° C. was added a solution of methyl 4,6-dichloronicotinate (13.1 g, 64mmol) in Et₂O (100 mL) dropwise with stirring. The resulting solutionwas heated at reflux for one hour. The reaction mixture was quenchedwith 100 mL of H₂O/ice. The resulting solution was extracted with EtOAc(2×500 mL). The organic layers were combined, dried over Na₂SO₄ andconcentrated in vacuo to afford 4.5 g (43%) of(4,6-dichloropyridin-3-yl)methanol.

Step 2

2,4-Dichloro-5-trichloromethyl-pyridine: To a solution of(4,6-dichloropyridin-3-yl)methanol (7 g, 39 mmol) in CCl₄ (200 mL), wasadded sulfuryl dichloride (120 mL) dropwise with stirring. The resultingsolution was heated at reflux overnight. The mixture was concentratedand the pH was adjusted to pH 8 by the addition of NaHCO₃ (2N). Theresulting solution was extracted with EtOAc (2×100 mL) and the organiclayers were combined and dried over Na₂SO₄. The residue was purified bysilica gel column chromatography to afford 1.2 g (12%) of2,4-dichloro-5-(trichloromethyl)pyridine.

Step 3

2,4-Dichloro-5-trifluoromethyl-pyridine: A 100 mL sealed tube purgedwith nitrogen containing 2,4-dichloro-5-(trichloromethyl)-pyridine (0.9g, 3.00 mmol) and SbF₅ (7 g, 30.00 mmol) was heated at 150° C. for 1 h.The reaction mixture was cooled and quenched by the adding 50 g ofH2O/ice after cooling. The pH was adjusted to pH=8 by the addition ofNaHCO₃. The resulting solution was extracted with EtOAc (2×100 mL). Thecombined organic layers were dried with MgSO₄ and concentrated in vacuoto give 0.5 g (62%) of 2,4-dichloro-5-(trifluoromethyl)-pyridine.

Step 4

1-(4-Chloro-5-trifluoromethyl-pyridin-2-yl)-cis-3,5-dimethyl-piperazine:2,4-dichloro-5-(trifluoromethyl)pyridine (800 mg, 3.70 mmol),2,6-dimethylpiperazine (800 mg, 7.14 mmol), and K₂CO₃ (1.0 g, 7.25 mmol)were added to dimethylformamide (15 mL). The resulting solution washeated for 2 h at 140° C. The reaction mixture was then quenched by theadding 50 mL of ice-water and extracted with EtOAc (50 mL). The organiclayers were combined and dried over MgSO₄. The solvent was concentratedand the residue was purified using silica gel column chromatography to0.2 g (18%) of1-(4-chloro-5-(trifluoromethyl)pyridine-2-yl)-cis-3,5-dimethylpiperazine.

Step 5

4-[4-(4-Chloro-5-trifluoromethyl-pyridin-2-yl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indan-2-carboxylicacid: The compound4-[4-(4-Chloro-5-trifluoromethyl-pyridin-2-yl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indan-2-carboxylicacid was prepared according to the procedure outlined in Example 79using indane-2-carboxylic acid methyl ester. ¹H NMR (CD₃OD) δ 8.26 (s, 1H), 7.67 (d, 1 H), 7.42 (d, 1 H), 7.29 (t, 1 H), 6.86 (s, 1 H) 4.22 (m,1 H), 4.08 (d, 2 H), 3.52 (d, 2 H), 3.34 (m, 2 H), 3.24 (m, 2 H), 3.17(dd, 2 H), 1.36 (d, 6 H).

EXAMPLE 108

4-[cis-2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid amide. Thionyl chloride (42 μL, 0.577 mmol) was added to4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid (250 mg, 0.502 mmol) in THF (4 mL) at 50 C for 1 h and thenconcentrated. The crude mixture was then dissolved in THF (4 mL) andammonium hydroxide (300 μL) was added. The cloudy brown solution wasstirred for an additional 3 h at room temperature. The solution was thenconcentrated and purified by silica gel column chromatography (0-20%MeOH in dichloromethane) to afford4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid amide (190 mg, 76%). ¹H NMR (400 MHz, CD₃OD) δ ppm. 7.71 (d, 1H),7.47 (d, 1H), 7.34 (t, 1H), 7.10 (d, 2H), 6.94-6.91 (m, 2H), 4.20-4.14(m, 1H), 4.05-3.90 (m, 1H), 3.54 (d, 2H), 3.41-3.21 (m, 5H), 2.77 (dd,1H), 2.68 (dd, 1H), 1.51 (d, 3H), 1.49 (d, 3H). LCMS: 498.7 (M+1)⁺.

EXAMPLE 109

cis-2,6-Dimethyl-1-[2-(1H-tetrazol-5-yl)-indane-4-sulfonyl]-4-(4-trifluoromethoxy-phenyl)-piperazine

Step 1

4-[cis-2,6-Dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carbonitrile.Triethylamine (200 μL, 1.4349 mmol) and phosphorus oxychloride (74 μL,0.7939 mmol) were added to a solution of4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid amide (254 mg, 0.5105 mmol) in dichloroethane (3 mL). The reactionwas stirred for 4 h at room temperature then directly purified by silicagel column chromatography (0-50% EtOAc in hexanes) to afford4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carbonitrile(23 mg, 9%). ¹H NMR (400 MHz, CD₃OD) δ ppm 7.77 (d, 1H), 7.54 (d, 1H),7.42 (t, 1H), 7.10 (d, 2H), 6.93 (d, 2H), 4.20-4.00 (m, 2H), 3.65-3.60(m, 1H), 3.60-3.40 (m, 2H), 3.40-3.20 (m, 4H), 2.80-2.60 (m, 2H), 1.50(d, 6H). LCMS: 480.0 (M+1)⁺.

Step 2

cis-2,6-Dimethyl-1-[2-(1H-tetrazol-5-yl)-indane-4-sulfonyl]-4-(4-trifluoromethoxy-phenyl)-piperazine:To a solution of4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carbonitrile(23 mg, 0.0440 mmol) in toluene (1 ml) was added dibutyltin oxide (13mg, 0.0281 mmol) and azidotrimethylsilane (5 μL, 0.0377 mmol). Thereaction mixture was stirred at 105° C. for 20 h upon which anadditional amount of dibutyltin oxide (13 mg, 0.0281 mmol) andazidotrimethylsilane (25 μL, 0.1884 mmol) was added and stirred at 105°C. for 4 h. The reaction mixture was cooled to room temperature and thendirectly purified by silica gel column chromatography (0-10% MeOH indichloromethane) to affordcis-2,6-dimethyl-1-[2-(1H-tetrazol-5-yl)-indane-4-sulfonyl]-4-(4-trifluoromethoxy-phenyl)-piperazine(14 mg, 61%). ¹H NMR (400 MHz, CD₃OD) δ ppm 7.75 (d, 1H), 7.54 (d, 1H),7.39 (t, 1H), 7.09 (d, 2H), 6.90 (d, 2H), 4.18-4.02 (m, 3H), 3.89 (dd,1H), 3.59-3.51 (m, 2H), 3.36-3.31 (m, 3H), 2.66-2.60 (m, 2H), 1.48 (d,6H). LCMS: 523.11 (M+1)⁺.

EXAMPLE 110

{5-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid: The compound{5-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-aceticacid was synthesized according to the procedure in Example 37 using(5-chlorosulfonyl-benzo[b]thiophen-3-yl)-acetic acid methyl ester andcis-3,5-dimethyl-1-(4-trifluoromethoxy-benzyl)-piperazine from Example95, Step 1. ¹H NMR (400 MHz, CD₃OD) δ 8.48 (s, 1H), 7.96 (d, 1H),7.88-7.80 (m, 2H), 7.57 (d, 2H), 7.28 (d, 2H), 4.60-4.50 (m, 2H), 4.36(s, 2H), 3.97 (s, 2H), 3.38-3.28 (m, 2H), 2.74-2.64 (m, 2H), 1.55 (d,6H); LCMS 542.9 (M+1)⁺.

EXAMPLE 111

4-[-3(3,4-Dichloro-benzyl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indain-2-carboxylicacid: The compound4-[-3(3,4-dichloro-benzyl)-cis-2,6-dimethyl-piperazine-1-sulfonyl]-indain-2-carboxylicacid was synthesized according to the procedure in Example 95 using3,4-dichloro-benzaldehyde. ¹H NMR (400 MHz, CD₃OD) δ 7.67 (d, 1H), 7.57(s, 1H), 7.56-7.46 (m, 2H), 7.36-7.28 (m, 2H), 4.38-4.22 (m, 1H),4.18-4.01 (m, 1H), 3.90-3.70 (m, 1H), 3.52-3.20 (m, 6H), 2.98-2.80 (m,2H), 2.50-2.30 (m, 2H), 1.51 (d, 6H); LCMS 499.8 (M+1)⁺.

EXAMPLE 112

4-[4-(3-Trifluomethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid

Step 1

Toluene-4-sulfonic acid trifluoromethyl ester: To a solution of2,2,2-trifluoroethanol (5 g, 50.00 mmol) in methylene chloride (20 mL)was added 4-methylbenzene-1-sulfonyl chloride (9.4 g, 49.21 mmol).Triethylamine (15 g, 148.51 mmol) was added and the resulting solutionwas stirred overnight. Water (50 mL) was added and the resultingsolution was extracted with methylene chloride (2×20 mL). The combinedorganic layers were dried (Na₂SO₄) and concentrated in vacuo to afford10 g (78.7%) of 2,2,2-trifluoroethyl 4-methylbenzenesulfonate.

Step 2

1-Bromo-3-(2,2,2-trifluoroethoxy)benzene: To a solution of2,2,2-trifluoroethyl 4-methylbenzenesulfonate (3 g, 11.81 mmol) indimethylformamide (20 mL) was added 3-bromophenol (1 g, 5.78 mmol) andNaOH (500 mg, 12.50 mmol). The resulting solution was stirred at 100° C.for 3 h. The reaction mixture was quenched by the adding H₂O (100 mL)and extracted with methylene chloride (3×50 mL). The combined organiclayers were dried (Na₂SO₄) and concentrated, and the residue purified bysilica gel column chromatography (1:20 EtOAc/petroleum ether) to provide1.1 g (31%) of 1-bromo-3-(2,2,2-trifluoroethoxy)benzene.

Step 3

4-{4-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-piperazine-1-sulfonyl}-indan-2-carboxylicacid. The compound4-{4-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-piperazine-1-sulfonyl}-indan-2-carboxylicacid was prepared according to the procedure outlined in Example 26using indane-2-carboxylic acid methyl ester. ¹H NMR (CD₃OD) δ 7.61 (d, 1H), 7.52 (d, 1 H), 7.14 (t, 1 H), 6.60 (dd, 1 H), 6.54 (t, 1 H), 6.47(dd, 1 H), 4.45 (q, 2 H), 3.56 (m, 2 H), 3.35 (m, 2 H), 3.21 (m, 8 H).

EXAMPLE 113

Step 1

1-Iodo-3-(trifluoromethoxy)benzene: To 3-(trifluoromethoxy)benzenamine(17.7 g, 100.00 mmol) was added a solution of NaNO₂ (7.4 g, 115.62 mmol)in H₂O (80 ml). H₂SO₄ (25 g, 250.00 mmol) was added dropwise withstirring at −5° C. The resulting solution was kept at −5° C. for 15minutes. To this solution was added a solution of KI (20 g, 120.48 mmol)in H₂O (60 ml) dropwise. The resulting solution was stirred overnight atroom temperature and extracted with EtOAc (2×100 mL). The combinedorganic layers were washed with Na₂SO₃/H₂O (2×50 mL), dried over Na₂SO₄and concentrated in vacuo. The residue was purified by silica gel columnchromatography to afford 4.0 g (14%) of1-iodo-3-(trifluoromethoxy)benzene.

Step 2

4-[4-(3-Trifluomethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid. The compound4-[4-(3-Trifluomethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid was prepared according to the procedure outlined in Example 26using indane-2-carboxylic acid methyl ester. ¹H NMR (CD₃OD) δ 7.61 (dd,1 H), 7.52 (dd, 1 H), 7.39 (t, 1 H), 7.26 (t, 1 H), 6.90 (dd, 1 H), 6.78(s, 1 H), 6.69 (dd, 1 H), 3.56 (m, 2 H), 3.36 (m, 2 H), 3.24 (m, 8 H).

EXAMPLE 114

4-{4-[4-(2,2,2-Trifluoro-ethoxy)-phenyl]-piperazine-1-sulfonyl}-indan-2-carboxylicacid: The compound4-{4-[4-(2,2,2-Trifluoro-ethoxy)-phenyl]-piperazine-1-sulfonyl}-indan-2-carboxylicacid was prepared according to the procedure outlined in Example 112using indane-2-carboxylic acid methyl ester and1-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-piperazine. ¹H NMR (CD₃OD) δ 7.61(dd, 1 H), 7.53 (dd, 1 H), 7.39 (m, 4 H) 4.41 (q, 2 H), 3.56 (m, 2 H),3.37 (m, 2 H), 3.20 (m, 4 H), 3.10 (m, 4 H).

EXAMPLE 115

4-[cis-2,6-Dimethyl-4-(3-trifluoromethoxyphenyl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid. The title compound was prepared according to the procedureoutlined in Example 113 using indane-2-carboxylic acid methyl ester andcis-3,5-dimethyl-1-(3-trifluoromethoxy-phenyl)-piperazine. ¹H NMR(CD₃OD) δ 7.71 (d, 1 H), 7.46 (d, 1 H), 7.34 (t, 1 H), 7.25 (t, 1 H),6.85 (dd, 1 H), 6.87 (s, 1 H), 6.67 (d, 1 H), 4.18 (m, 1 H), 4.03 (m, 1H), 3.53 (d, 1 H), 3.41 (m, 2 H), 3.35 (m, 2 H), 2.81 (dd, 1 H), 2.73(dd, 2 H), 1.48 (dd, 6 H).

EXAMPLE 116

4-[2S,5S-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid

Step 1

2S,5S-Dimethyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine:2-chloro-5-trifluoromethyl-pyridine (330 mg, 1.8 mmol),2S,5S-dimethyl-piperazine dihydrobromide (1.0 g, 3.6 mmol), potassiumcarbonate (2.0 g, 14 mmol), and DMF (8 mL) were heated at 100° C. undernitrogen for 9.5 h. The mixture was allowed to cool to room temperature,filtered through Celite with dichloromethane, and concentrated in vacuo.The residue was purified by silica gel chromatography (1:0→4:1;dichloromethane:methanol) to give2S,5S-dimethyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine: MS (ESI):259.8 (M+H).

Step 2

4-[2S,5S-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2(R,S)-carboxylicacid methyl ester: A solution of4-chlorosulfonyl-indan-2(R,S)-carboxylic acid methyl ester (250 mg, 0.91mmol) and THF (2 mL) was added to a solution of2S,5S-dimethyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (150 mg,0.58 mmol), triethylamine (0.30 mL, 2.2 mmol) and THF (8 mL) at to roomtemperature under nitrogen. After 2 h, silica gel was added, and themixture was concentrated in vacuo. Purification by silica gelchromatography (99:1→9:1; CH₂Cl₂:methanol) gave4-[2S,5S-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2(R,S)-carboxylicacid methyl ester: MS (ESI): 498.5 (M+H).

Step 3

4-[2S,5S-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2(R,S)-carboxylicacid: A mixture of4-[2S,5S-Dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid methyl ester (97 mg, 0.19 mmol), 1N LiOH (2 mL), tetrahydrofuran (8mL), and methanol (2 mL) was stirred at to room temperature for 2 h. Thereaction was poured into 1N HCl (40 mL) and extracted with ethyl acetate(40 mL×2). The combined organic extracts were dried, filtered, andconcentrated in vacuo to give4-[2S,5S-dimethyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2(R,S)-carboxylicacid: ¹H NMR (400 MHz, DMSO-d6): δ 8.16 (s, 1H), 8.12 (s, 1H), 7.54-7.43(m, 4H), 7.12 (d, 1H), 7.11 (d, 1H), 7.01 (app td, 2H), 6.32 (d, 1H),6.28 (d, 1H), 4.38-4.24 (m, 2H), 4.02-3.66 (m, 6H), 3.50-3.32 (m, 2H),3.26-3.10 (m, 5H), 3.06-2.94 (m, 3H), 2.92-2.82 (m, 3H), 2.82-2.72 (m,1H), 1.22-1.15 (m, 6H), 0.98 (d, 3H), 0.96 (d, 3H); MS (ESI): 484.4(M+H).

EXAMPLE 117

4-[3-(4-Trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-sulfonyl]-indan-2-carboxylic acid

Step 1

cis-1-benzyl-piperidine-2,6-dicarboxylic acid hydrochloride: A mixtureof cis-1-benzyl-piperidine-2,6-dicarboxylic acid dimethyl ester (2.33 g,8 mmol) and 6N HCl (28 mL) was heated at 115° C. for 14 h. The resultingsolution was cooled to 0° C. and stirred for 2 h. The white precipitatewas filtered and dried to give cis-1-benzyl-piperidine-2,6-dicarboxylicacid hydrochloride: MS (ESI): 264.5 (M+H).

Step 2

9-benzyl-3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione: 1,1-Carbonyl diimidazole (CDI; 1.2 g, 7.4 mmol)was added to a mixture of cis-1-benzyl-piperidine-2,6-dicarboxylic acidhydrochloride (1.0 g, 3.34 mmol) and dioxane (10 mL) at rt under N₂. Themixture was heated at 100° C. After 15 min, a solution of4-trifluoromethoxyaniline (600 mg, 3.39 mmol) and dioxane (2 mL) wasadded. After an additional 2 h, CDI (500 mg, 3.08 mmol) was added(Caution: CO₂ evolution). After an additional 1 h, the reaction wasallowed to cool to rt, concentrated, diluted with ethyl acetate (120 mL)and washed with 0.5N HCl (100 mL×2). The organic extract was dried,filtered, concentrated, and purified by silica gel chromatography(1:0→4:1; hexanes:ethyl acetate) to give9-benzyl-3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione:MS (ESI): 405.4 (M+H).

Step 3

3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo [3.3.1]nonane-2,4-dione:A mixture of9-benzyl-3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione(120 mg, 0.3 mmol), 10% Pd/C (20 mg, 0.02 mmol Pd), ethyl acetate (8mL), and ethanol (2 mL) were stirred vigorously under an atmosphere ofH₂. After 2 h, more ethanol (2 mL) was added. After an additional 16 h,the reaction was filtered through Celite and concentrated to give3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione:MS (ESI): 315.4 (M+H).

Step 4

3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane: A solutionof3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione(80 mg, 0.25 mmol) and THF (4 mL) was heated at 70° C. under N₂. Asolution of BH₃.SMe₂ (2M in THF, 0.4 mL, 0.8 mmol) was added dropwise.After 40 min, 6N HCl (1.0 mL) was added dropwise (Caution: H₂evolution). After an additional 30 min, the reaction was poured into 1NNaOH (8 mL) and extracted with dichloromethane (30 mL×2). The combinedorganic extracts were dried, filtered and concentrated to give3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane: MS (ESI):287.5 (M+H).

Step 5

4-[3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-sulfonyl]-indan-2-carboxylic acid methyl ester: Amixture of 3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane(60 mg, 0.21 mmol), 4-chlorosulfonyl-indan-2(R,S)-carboxylic acid methylester (120 mg, 0.44 mmol), potassium carbonate (200 mg, 1.4 mmol), andacetonitrile (3 mL) were heated at 50° C. for 2 h. The mixture wasfiltered through Celite, concentrated, and purified by silica gelchromatography (9:1→4:1; hexanes:ethyl acetate) to give4-[3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-sulfonyl]-indan-2-carboxylicacid methyl ester: MS (ESI): 525.5 (M+H).

Step 6

4-[3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-sulfonyl]-indan-2-carboxylic acid: A mixture of4-[3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-sulfonyl]-indan-2-carboxylicacid methyl ester (13 mg, 0.025 mmol), 1N LiOH (2 mL), tetrahydrofuran(8 mL), and methanol (2 mL) was stirred at rt for 3 h. The reaction waspoured into 1N HCl (40 mL) and extracted with ethyl acetate (40 mL×2).The combined organic extracts were dried, filtered, and concentrated togive 4-[3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-sulfonyl]-indan-2-carboxylic acid: ¹H NMR (400 MHz,DMSO-d6): δ 7.69 (d, 1H), 7.52 (d, 1H), 7.38 (t, 1H), 7.19 (d, 2H), 6.92(d, 2H), 4.04-3.97 (m, 2H), 3.74-3.67 (m, 2H), 3.44-3.30 (m, 3H),3.26-3.10 (m, 2H), 2.96-2.86 (m, 2H), 2.26-2.15 (m, 1H), 1.86-1.72 (m,4H), 1.51-1.43 (m, 1H); MS (ESI): 511.4 (M+H).

Additional compounds, like those disclosed below, can be made using themethods described above. It is expected that these compounds when madewill have activity similar to those that have been made in the examplesabove. Such compounds have the structure A-B-C-D, wherein:

A is selected from the group consisting of

B is selected from the group consisting of

C is selected from the group consisting of

and

D is selected from the group consisting of

The compounds in Examples 1-117 have been shown to be PPAR modulatorsusing the following assays. The other compounds listed above, some ofwhich have not yet been made and/or tested, are predicted to haveactivity in these assays as well.

In Vitro Biological Activity Assay

Compounds may be screened for functional potency in transienttransfection assays in CV-1 cells for their ability to activate the PPARsubtypes (transactivation assay). A previously established chimericreceptor system was utilized to allow comparison of the relativetranscriptional activity of the receptor subtypes on the same syntheticresponse element and to prevent endogenous receptor activation fromcomplicating the interpretation of results. See, for example, Lehmann,J. M.; Moore, L. B.; Smith-Oliver, T. A; Wilkinson, W. O.; Willson, T.M.; Kliewer, S. A., An antidiabetic thiazolidinedione is a high affinityligand for peroxisome proliferator-activated receptor δ (PPARδ), J.Biol. Chem., 1995, 270, 12953-6. The ligand binding domains for murineand human PPAR-alpha, PPAR-gamma, and PPAR-delta are each fused to theyeast transcription factor GAL4 DNA binding domain. CV-1 cells weretransiently transfected with expression vectors for the respective PPARchimera along with a reporter construct containing four or five copiesof the GAL4 DNA binding site driving expression of luciferase. After8-16 h, the cells are replated into multi-well assay plates and themedia is exchanged to phenol-red free DME medium supplemented with 5%delipidated calf serum. 4 hours after replating, cells were treated witheither compounds or 1% DMSO for 20-24 hours. Luciferase activity wasthen assayed with Britelite (Perkin Elmer) following the manufacturer'sprotocol and measured with either the Perkin Elmer Viewlux or MolecularDevices Acquest (see, for example, Kliewer, S. A., et. al. Cell 1995,83, 813-819). Rosiglitazone is used as a positive control in the PPARδassay. Wy-14643 and GW7647 is used as a positive control in the PPARδassay. GW501516 is used as the positive control in the PPARδ assay.

Compounds of Examples 1-117 were assayed to measure their biologicalactivity with respect to their EC₅₀ values for modulating PPAR-alpha,PPAR-gamma, and PPAR-delta as set forth in Table 1.

TABLE 1 Biological Activity PPAR alpha PPAR delta PPAR gamma A > 100 μMA > 100 μM A > 100 μM Example B = 5-100 μM B = 5-100 μM B = 5-100 μM # C= <5 μM C = <5 μM C = <5 μM 1 B B B 2 A C B 3 B B B 4 A B A 5 B C B 6 AC C 7 B C B 8 B C C 9 B C B 10 B C C 11 B C C 12 A B A/B 13 B C B 14 A BB 15 B B B 16 B C B 17 B B B 18 B C B 19 C C C 20 C C C 21 B B B 22 C CB 23 C C C 24 C C C 25 C C C 26 C C C 27 B C B 28 A C B 29 B B B 30 B BB 31 A B A 32 A C B 33 A C B 34 A C B 35 B C B 36 A A B 37 B C C 38 C CC 39 C C C 40 C C C 41 B C B 42 B C B 43 A C B 44 A C B 45 C C C 46 C CC 47 C C C 48 C C C 49 C C B 50 B C B 51 C C B 52 C C C 53 C C C 54 C CC 55 C C C 56 C C C 57 C C C 58 C C B 59 C C B 60 C C B 61 C C C 62 C CB 63 C C C 64 C C C 65 C C C 66 C C B 67 C C C 68 C C C 69 C C C 70 C CB 71 C C C 72 C C C 73 B C C 74 C C C 75 B C B 76 A C A 77 A C A 78 B CB 79 A C A 80 A C A 81 A C A 82 A C A 83 B C B 84 A B B 85 B C B 86 C CC 87 B C C 88 A C B 89 C C C 90 B C B 91 B C C 92 B C B 93 B C B 94 B CB 95 B C B 96 A C B 97 B C B 98 B C C 99 B C B 100 B C B 101 B C B 102 CC C 103 B C B 104 C C B 105 B C B 106 B C B 107 A C A 108 B C B 109 A CB 110 A C B 111 A C B 112 B B B 113 B C B 114 B B B 115 A C B 116 B C B117 B C B

In Vivo Assay

Evaluation of Pharmacological Efficacy of a Compound of the Invention ina Model of Diet-Induced Obesity (DIO) in Mice

The DIO model in mice exhibits several features that are hallmark ofmetabolic syndrome in humans. Metabolic syndrome in humans ischaracterized by abdominal obesity, high triglycerides, impaired fastingglucose and hyperinsulinemia. In the DIO model, mice are fed high fatdiet (HFD, Research diet D12492, Research Diet, NJ) diet (58% lard) forthe entire period of the study. Compared to normal chow (NC,Harlan-Tekland #8604, WI) fed animals the HF fed mice develop severalfeatures of metabolic syndrome such as, hypertriglyceridemia,hyperinsulinemia and mild hyperglycemia, as early as two weeks, on thisdiet. Body mass analyses demonstrate that the mice also develop astriking increase in visceral obesity by weeks 3-4 of HF feeding. Thismodel was used to evaluate the pharmacological effects of a compound ofthe invention selected from the group consisting of Examples 1-117(referred to for the purposes of this study as “Compound (I)”) inmitigating several features of HFD induced metabolic syndrome inrodents.

C57Bl/6j mice (n=5) were fed ad libitum with either the HFD (58% fat) orNC (5%) diet for 3 weeks prior to start of experiment, and throughoutthe course of the experiment (45 days). Starting on Day 1, mice weredosed BID with either Compound (I)+vehicle, vehicle alone, or GW501516,a known PPARδ modulator in clinical development by Glaxo-Wellcome, forthe entire period of the study. Animals were the assessed for bodyweight gain, food intake, triglyceride (TG), insulin, and glucose levelsunder fasting and postprandial (PP) conditions. Animals were weighedtwice weekly in the morning to determine body weight gain. Plasma orserum was separated from whole blood (Sarstedt) and TG levels wereassayed with a TG kit (Thermo Electron Corporation, TX). Plasma insulinlevels were assayed using the ultrasensitive mouse Insulin ELISAimmunoassay (American Laboratory Products Company). Total cholesterol,HDLc and LDLc was measured to evaluate pharmacological efficacy atvarious time points during the study and serum transaminases weremeasured to evaluate any potential toxicity of the compound. Thesemeasurements were performed with a chemistry analyzer at Labcorp ofAmerica, NC. The pharmacological efficacy of the compound in the doseranging study is summarized in Table 2:

TABLE 2 Com- % change pound in body Dose, or weight TG Insulin GroupDiet mg/kg Vehicle (d0 vs d40) (mg/dl) (ng/ml) 1 NC — Vehicle 13.1 156 ±33 0.6 ± 0.2 2 NC 4.5 Com- 7.6 129 ± 17 0.3 ± 0.1 pound (I) 3 HFD —Vehicle 30.2 301 ± 40 1.4 ± 0.4 4 HFD 1.5 Com- 13.8 264 ± 25 1.4 ± 0.2pound (I) 5 HFD 3.0 Com- 9.7 177 ± 33 0.9 ± 0.3 pound (I) 6 HFD 4.5 Com-10.1 175 ± 48   1 ± 0.2 pound (I) 7 HFD 1.5 GW516 10.6 268 ± 56 1.3 ±0.3

Compound (I) lowered hepatic glucose output in a glucose tolerance test(IPGTT) performed using a bolus of glucose (2 mg/kg) in mice fastedovernight and demonstrated improved insulin sensitivity over the HFDvehicle group in insulin tolerance testing (IPITT) conducted withinsulin at 1 U/Kg. The compound had no effect on fasted or PP glucoselevels but showed significant reduction in body weight gain, visceralobesity, triglyceride and insulin levels induced by the HFD. In additionwe observed a significant reversal of HFD-induced insulin resistance inthe mice treated with the compound.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A compound having structural Formula (I)

Or a pharmaceutically acceptable salt, or ester thereof, wherein; A is asaturated or unsaturated hydrocarbon chain having from 3 to 5 atoms,forming a five- to seven-membered ring; T is selected from the groupconsisting of —C(O)OH, —C(O)NH₂, and tetrazole; G₁ is selected from thegroup consisting of —(CR¹R²)_(n)—, —Z(CR¹R²)_(n)—, —(CR¹R²)_(n)Z—,—(CR¹R²)_(r)Z(CR¹R²)_(s)—; Z is O, S or NR; n is 0, 1, or 2; r and s areindependently 0 or 1; R¹ and R² are independently selected from thegroup consisting of hydrogen, halo, optionally substituted lower alkyl,optionally substituted lower heteroalkyl, optionally substituted loweralkoxy, and lower perhaloalkyl or together may form an optionallysubstituted cycloalkyl; X₁, X₂, and X₃ are independently selected fromthe group consisting of hydrogen, optionally substituted lower alkyl,optionally substituted cycloalkyl, halogen, perhaloalkyl, hydroxy,optionally substituted lower alkoxy, nitro, cyano, and NH₂; G₂ isselected from the group consisting of a saturated or unsaturatedheterocycloalkyl linker, optionally substituted with X₄ and X₅; X₄ andX₅ are independently selected from the group consisting of hydrogen,optionally substituted lower alkyl, halogen, lower perhaloalkyl,hydroxy, optionally substituted lower alkoxy, nitro, cyano, NH₂, andCO₂R, or X₄ and X₅ together may form a carbocycle; R is selected fromthe group consisting of optionally substituted lower alkyl and hydrogen;G₃ is selected from the group consisting of a bond, a double bond,—(CR³R⁴)_(m)—, carbonyl, and —(CR³R⁴)_(m)CR³═CR⁴—; m is 0, 1, or 2; R³and R⁴ are independently selected from the group consisting of hydrogen,optionally substituted lower alkyl, optionally substituted lower alkoxy,optionally substituted aryl, lower perhaloalkyl, cyano, and nitro; G₄ isselected from the group consisting of hydrogen, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedcycloalkyl, optionally substituted cycloheteroalkyl, optionallysubstituted cycloheteroaryl, optionally substituted cycloalkenyl, and—N═(CR⁵R⁶); and R⁵ and R⁶ are independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, optionally substituted cycloalkenyl, andoptionally substituted cycloheteroalkyl.
 2. A compound as recited inclaim 1 wherein T is —C(O)OH.
 3. A compound as recited in claim 2wherein A is a chain having three atoms and forming a five-memberedring.
 4. A compound as recited in claim 3 having the followingstructural formula:


5. A compound as recited in claim 4 having a structural formula selectedfrom the group consisting of:


6. A compound as recited in claim 4 having a structural formula selectedfrom the group consisting of:


7. A compound as recited in claim 2, wherein: G₁ is —(CR¹R²)_(n)—; Withthe proviso that if A is a 5 carbon chain, n is 0 or 1; G₂ has thestructure:

Y₁ is N; and Y₂ is selected from the group consisting of N and C—X₆; X₄and X₅ are independently selected from the group consisting of hydrogen,optionally substituted lower alkyl, halogen, lower perhaloalkyl,hydroxy, optionally substituted lower alkoxy, nitro, cyano, NH₂, andCO₂R, or X₄ and X₅ together may form a carbocycle; R is selected fromthe group consisting of lower alkyl and hydrogen; p is 1, 2 or 3; W isselected from the group consisting of —CX₄X₅— and N—X₇; X₄ and X₅ areindependently selected from the group consisting of hydrogen, optionallysubstituted lower alkyl, halogen, lower perhaloalkyl, hydroxy,optionally substituted lower alkoxy, nitro, cyano, NH₂, and CO₂R; X₆ isselected from the group consisting of hydrogen, alkyl, hydroxy, alkoxy,cyano, halogen, lower perhaloalkyl and NH₂ or null when forming a doublebond with an adjacent ring atom; and X₇ is selected from the groupconsisting of hydrogen, alkyl, hydroxy, and lower perhaloalkyl, or nullwhen forming a double bond with Y₂.
 8. The compound as recited in claim7 wherein A is a chain having three atoms and forms a five-memberedring.
 9. The compound as recited in claim 8 wherein G₃ is a bond. 10.The compound as recited in claim 9 wherein: p is 2; and W is CX₄X₅. 11.The compound as recited in claim 10 wherein G₄ is optionally substitutedaryl or optionally substituted heteroaryl.
 12. The compound as recitedin claim 11 wherein G₄ is singly or doubly substituted with halogen,lower alkyl, lower perhaloalkyl, lower perhaloalkoxy or mono- ordi-haloalkoxy.
 13. The compound as recited in claim 10 wherein Y₂ is N.14. The compound as recited in claim 13 wherein G₄ is selected from thegroup consisting of optionally substituted aryl and optionallysubstituted heteroaryl.
 15. The compound as recited in claim 14 whereinG₄ is optionally substituted phenyl or optionally substituted pyridinyl.16. The compound as recited in claim 15 wherein G₄ is singly or doublysubstituted with halogen, lower alkyl, lower perhaloalkyl, or lowerperhaloalkoxy or mono- or di-haloalkoxy.
 17. A compound as recited inclaim 1 wherein R¹ and R² are independently selected from the groupconsisting of hydrogen, methyl, ethyl, and propyl, or together may forma cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
 18. A compound asrecited in claim 17, wherein R¹ and R² are hydrogen.
 19. A compound asrecited in claim 1 wherein X₁, X₂, and X₃ are each independentlyselected from the group consisting of hydrogen, lower alkyl,perhaloalkyl, and halogen.
 20. A compound as recited in claim 19,wherein X₁, X₂, and X₃ are independently selected from the groupconsisting of hydrogen and methyl.
 21. The compound as recited in claim3, having a structural formula selected from the group consisting of:

wherein G₁ is selected from the group consisting of —(CR¹R²)_(n)— and—(CR¹R²)_(n)O—.
 22. The compound as recited in claim 21, wherein G₁ is—(CR¹R²—)_(n)—, and n is 0 or
 1. 23. The compound as recited in claim22, wherein at least one of X₄ and X₅ is not hydrogen.
 24. The compoundas recited in claim 23, wherein said at least one of X₄ and X₅ is loweralkyl.
 25. The compound as recited in claim 24, wherein said at leastone of X₄ and X₅ is methyl.
 26. The compound as recited in claim 25,wherein one X₄ and one X₅ are methyl.
 27. The compound as recited inclaim 26, wherein G₂ is piperazine, and X₄ and X₅ are methyl and areattached to the piperazine ring at the 2 and 6 positions.
 28. Thecompound as recited in claim 26, wherein G₂ is piperazine, and X₄ and X₅are methyl and are attached to the piperazine ring at the 3 and 5positions.
 29. The compound as recited in claim 26, wherein G₂ ispiperazine, and X₄ and X₅ are methyl and are attached to the piperazinering at the 2 and 3 positions.
 30. The compound as recited in claim 26,wherein the X₄ and X₅ methyl groups are oriented cis to each other. 31.A compound as recited in claim 23, wherein R¹ and R² are independentlyselected from the group consisting of hydrogen, methyl, ethyl, andpropyl, or together may form a cyclopropyl.
 32. A compound as recited inclaim 31, wherein R¹ and R² are hydrogen.
 33. A compound as recited inclaim 22, wherein X₁, X₂, and X₃ are independently selected from thegroup consisting of hydrogen, halogen, optionally substituted loweralkyl, and optionally substituted lower alkoxy.
 34. A compound asrecited in claim 22, wherein G₃ is a bond.
 35. A compound as recited inclaim 22 wherein G₄ has a structural formula selected from the groupconsisting of:

q is 1 to 3; X₈ and X₉ are independently selected from the groupconsisting of hydrogen, alkyl, halogen, lower perhaloalkyl, lowerperhaloalkoxy or mono- or di-haloalkoxy, hydroxy, alkoxy, nitro, cyano,NH₂, and CO₂R; and R is selected from the group consisting of loweralkyl and hydrogen.
 36. The compound as recited in claim 1 selected fromthe group consisting of


37. The compound as recited in claim 36 wherein said compound is4-[4-(4-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylicacid.
 38. The compound as recited in claim 1 wherein A is a saturated orunsaturated hydrocarbon chain having from 3 to 5 atoms, forming a five-to seven-membered ring; T is —C(O)OH; G₁ is selected from the groupconsisting of —(CR¹R²)_(n)—, —Z(CR¹R²)_(n)—, —(CR¹R²)_(n)Z—,—(CR¹R²)_(r)Z(CR¹R²)_(s)—; Z is O, S or NR; n is 0, 1, or 2; r and s areindependently 0 or 1; R¹ and R² are independently selected from thegroup consisting of hydrogen, halo, lower alkyl, lower alkoxy, and lowerperhaloalkyl or together may form an optionally substituted cycloalkyl;X₁, X₂, and X₃ are independently selected from the group consisting ofhydrogen, lower alkyl, cycloalkyl, halogen, perhaloalkyl, hydroxy, loweralkoxy, nitro, cyano, and NH₂; G₂ is selected from the group consistingof a saturated or unsaturated cycloalkyl or heterocycloalkyl linker,optionally substituted with X₄ and X₅; X₄ and X₅ are independentlyselected from the group consisting of hydrogen, alkyl, halogen, lowerperhaloalkyl, hydroxy, alkoxy, nitro, cyano, NH₂, and CO₂R; R isselected from the group consisting of lower alkyl and hydrogen; G₃ isselected from the group consisting of a bond and —(CR³R⁴)_(m)—; m is 0,1, or 2; R³ and R⁴ are independently selected from the group consistingof hydrogen, lower alkyl, lower alkoxy, optionally substituted aryl,lower perhaloalkyl, cyano, and nitro; and G₄ is selected from the groupconsisting of

q is 1 to 3; X₈ and X₉ are independently selected from the groupconsisting of hydrogen, alkyl, halogen, lower perhaloalkyl, lowerperhaloalkoxy or mono- or di-haloalkoxy, hydroxy, alkoxy, nitro, cyano,NH₂, and CO₂R; and R is selected from the group consisting of loweralkyl and hydrogen.
 39. The compound as recited in claim 1 wherein thecompound has the structure A-B-C-D and A is selected from the groupconsisting of

B is selected from the group consisting of

C is selected from the group consisting of a bond,

 and D is selected from the group consisting of


40. A pharmaceutical composition comprising a compound as recited inclaim 1 and a pharmaceutically acceptable carrier.